Protein Induced By Vitamin K absence-II Research Articles

Evaluation of Serum GDF15, AFP, and PIVKA-II as Diagnostic Markers for HBV-Associated Hepatocellular Carcinoma.

To evaluate the potential diagnostic value of growth differentiation factor 15 (GDF15) alone and its combination with protein induced by vitamin K absence-II (PIVKA-II) and alpha-fetoprotein (AFP) for hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Serum levels of GDF15, PIVKA-II, and AFP were measured in 110 patients with HBV-associated HCC, 70 patients with HBV-related liver cirrhosis (LC), 70 patients with chronic hepatitis B (CHB), and 110 healthy patients. Serum GDF15 was positively related to the levels of PIVKA-II and AFP in patients with HCC (r = 0.352 and r = 0.378; all P <.0001). When the receiver operating characteristic (ROC) curve was plotted for patients with HCC vs all control patients, serum GDF15 had diagnostic parameters of an area under the curve (AUC) of 0.693, a sensitivity of 67.30%, and a specificity of 66.70%, which were lower than parameters for PIVKA-II and AFP (all P <.0001). When the ROC curve was plotted for patients with HCC vs patients with LC, the combination of GDF15 and PIVKA-II had the highest diagnostic accuracy of AUC and specificity as compared with other combinations (all P <.0001). We found that GDF15 is a potent serum marker for the detection of HBV-associated HCC and that PIVKA-II combined with GDF15 can improve diagnostic accuracy for HBV-associated HCC.

Influence of Warfarin Therapy on Prothrombin Production and Its Posttranslational Modifications.

Protein induced by vitamin K absence-II (PIVKA-II) is produced by the liver during hepatoma and upon warfarin administration. Those patients have disturbed protein synthesis and glycosylation in the liver. This decreases the number of γ-carboxyglutamyl (Gla) residues on prothrombin, converting prothrombin into PIVKA-II. The mechanism of this conversion, however, is not clearly understood. Prothrombin was isolated from healthy and warfarin-treated individuals whose liver function of protein production was quantitatively normal. Glycan structures in the purified prothrombin containing PIVKA-II were qualitatively analyzed by high performance liquid chromatography after labeling the glycan with fluorophore 2-aminobenzamide. The concentration of PIVKA-II was significantly higher in the warfarin-treated individuals than in the healthy individuals (P< 0.001). Although protein production in the liver was normal in both groups, the concentration of prothrombin was lower in the warfarin-treated individuals than in the healthy individuals (P < 0.001). The main glycan was A2 in the healthy and warfarin-treated individuals (86.6 ± 4.4% and 85.6 ± 3.4%, respectively). Eight types of glycan were characterized in both groups, although generation of PIVKA-II in the warfarin-treated individuals did not lead to variation in glycosylation of prothrombin. Warfarin therapy leads to lower amounts of prothrombin and Gla residues within prothrombin without exerting qualitative and quantitative change in glycan profile and protein synthetic function in the liver.

Correlation of serum PIVKA-II and AFP level with portal vein tumor thrombus and BCLC stage in newly diagnosed hepatocellular carcinoma patients.

e16608 Background: Protein Induced by Vitamin K Absence-II (PIVKA-II) is a tumor marker specific for hepatocellular carcinoma (HCC). PIVKA-II levels correspond with HCC oncogenesis and disease progression. Portal vein tumor thrombus (PVTT) in patients with HCC is a significant factor that affect treatment and prognosis. In this study we assessed the predictive value of PIVKA-II and AFP for vascular invasion and BCLC stage in newly diagnosed HCC patients. Methods: We retrospectively reviewed records of newly diagnosed HCC patients at a tertiary hospital in India between January 2019 to December 2019. Clinical details, BCLC stage, radiological imaging records, serum levels of PIVKA-II and AFP at the time of diagnosis were obtained from medical records. Diagnostic accuracy and cut-off value of PIVKA-II in patients with portal invasion were calculated using receiver operator curve (ROC) analysis. Multiple pairwise comparisions between BCLC stage with PIVKA-II and AFP levels were analysed using Kruskal-Wallis test. Results: Out of 162 newly diagnosed HCC patients 42(25.9%) were detected with PVTT on imaging such as contrast-enhanced computed tomography or magnetic resonance imaging at the time of diagnosis.120(74.1%) patients without PVTT were taken as controls for the analysis. Serum level of PIVKA-II in HCC patients with PVTT was significantly higher than in HCC patients without PVTT (1152.57 mAU/ml vs 146.39 mAU/ml; p = 0.001). AUROC of PIVKA-II was 0.796 (95%CI 0.70-0.892, p = 0.000).The optimal cut-off value of PIVKA-II was 271.81 mAU/ml with a sensitivity of 78.6% and specificity of 52.4%, and the diagnostic accuracy was 59.98%. AUROC of AFP was 0.619 (95%CI 0.59-0.72, p = 0.001). Median PIVKA-II value increased from BCLC stage A to D. Kruskal-Wallis test showed a significant difference of PIVKA-II levels between all stages except stage A and B (p values for stage A-B (0.297), A-C (0.000), A-D(0.000),whereas for AFP results were significant only between stages A and C (p values for stage A-B (0.348), A-C (0.003), A-D(0.206). Conclusions: Serum PIVKA-II level appears as a good predictive marker for PVTT and BCLC stage when compared to AFP which may guide therapeutic strategy and assessment of prognosis in newly diagnosed HCC patients.

Renal metastasis from primary hepatocellular carcinoma: a case report.

We report a rare case of renal metastasis from primary hepatocellular carcinoma (HCC). A mass in the right kidney of a 71-year-old man was detected by follow-up computed tomography (CT) for HCC. He was diagnosed as having primary HCC 18years ago and had undergone partial hepatectomy, transarterial chemoembolization, and pulmonary segmentectomy for primary HCC and its metastasis over 10years. Eight years after this, follow-up CT revealed a right kidney mass, and laboratory testing showed an elevated level of protein induced by vitamin K absence II (PIVKA-II). We performed laparoscopic radical nephrectomy for the right kidney mass. Histopathology revealed renal metastasis from primary HCC. To date, only a small number of cases of renal metastasis from HCC have been reported.

Evaluation of Diagnostic Utility of Protein Induced by Vitamin K Absence–II (PIVKA-II) in Hepatocellular Carcinoma

Evaluation of Diagnostic Utility of Protein Induced by Vitamin K Absence–II (PIVKA-II) in Hepatocellular Carcinoma

Protein Induced by Vitamin K Absence II (PIVKA-II) as a potential serological biomarker in pancreatic cancer: a pilot study.

IntroductionProtein induced by vitamin K absence II (PIVKA-II) is an abnormal prothrombin increased in gastrointestinal malignancy. We aimed to evaluate PIVKA-II in comparison to established pancreatic cancer (PC) biomarkers (CA 19-9, carcinoembryonic antigen (CEA) and CA 242) measured in PC patients and in patients with benign pancreatic diseases.Materials and methodsWe studied 26 PC patients (Group 1) and 20 patients with benign pancreatic diseases (Group 2). PIVKA-II and CEA were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Gent, Belgium), CA 19-9 and CA 242 were measured by ELSA (CisBio Bioassays, Codolet, France) and EIA (Fujirebio Diagnostics AB, Göteborg, Sweden), respectively. Receiver operating characteristic (ROC) analysis was performed to assess biomarkers’ diagnostic characteristics in both groups.ResultsMedian and interquartile range (IQR) in Group 1 and Group 2 were: 1749.0 (320.2 – 3921.0) vs. 31.0 (23.0 – 43.0) mAU/mL (P < 0.001) for PIVKA-II, 260.0 (158.7 – 272.0) vs. 45.2 (9.0 – 58.0) U/mL (P = 0.034) for CA 19-9, 104.0 (30.2 – 150.0) vs. 7.2 (4.8 – 26.0) U/mL (P < 0.050) for CA 242, 9.4 (5.3 – 37.5) vs. 4.5 (1.8 – 7.0) ng/mL (P = 0.021) for CEA. Areas under the ROC curve of PIVKA-II, CA 19-9, CA 242, CEA were 0.86 (95% CI: 0.71 – 1.00), 0.58 (95% CI: 0.38 – 0.78), 0.73 (95% CI: 0.54 – 0.92), 0.64 (95% CI: 0.44 – 0.85), respectively.ConclusionsPIVKA-II is significantly higher in PC than in benign pancreatic diseases. PIVKA-II shows a rather good diagnostic performance compared to CA 19-9, CEA and CA242, thus its determination could help PC management.

PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients.

Protein induced by vitamin K absence-II (PIVKA-II) is a potential screening marker for hepatocellular carcinoma (HCC). Limited data are available about its utility in discriminating neoplastic from regenerative nodules at ultrasonography (US) evaluation in cirrhotic patients. Aim of this study was to investigate the diagnostic utility of PIVKA-II in cases showing liver nodules of uncertain diagnosis at US.Ninety cirrhotics with US evidence of liver nodule(s) were enrolled. All patients underwent blood sampling within 1 week of US and were thereafter followed up. HCC was confirmed in 40/90 cases, and in all cases it was in a very early/early stage. All sera were tested for PIVKA-II and alpha-fetoprotein (AFP) at the end of follow-up. PIVKA-II at a cut off of 60 mAU/mL was significantly associated with HCC at both univariate and multivariate analysis (P = .016 and P = .032, respectively). AFP at a cut off of 6.5 ng/mL was not associated with HCC at univariate analysis (P = .246). ROC curves showed that PIVKA-II had 60% sensitivity, 88% specificity, 80% positive predictive value (PPV), and 73% negative predictive value (NPV), whereas AFP had 67% sensitivity, 68% specificity, 63% PPV, and 72% NPV. AUROC curves showed that the combination of both biomarkers increased the diagnostic accuracy for HCC (AUC 0.76; sensitivity 70%, specificity 94%, PPV 91%, and NPV 79%).In conclusion, PIVKA-II is a useful tool for the diagnostic definition of US-detected liver nodules in cirrhotic patients, and it provides high diagnostic accuracy for HCC when combined with AFP.

Lower diastolic blood pressure in healthy subjects with vitamin K deficiency: a preliminary cross-sectional study

Introduction. There is a growing body of evidence for the role of vitamin K in cardiovascular health. As a cofactor of carboxylation of the matrix Gla protein it prevents arterial calcification. However, the data on the relationship between vitamin K status and the blood pressure are scarce, and particularly so in persons without the burden of cardiovascular risk factors. Material and Methods. We performed a pilot cross‑sectional study, in which we hypothesized that vitamin K deficiency is associated with a higher blood pressure in young, healthy people. The concentration of protein induced by vitamin K absence‑II (PIVKA‑II) larger than 2 ng/mL was chosen as a proxy for vitamin K deficiency; it was assessed in serum using ELISA. Blood pressure was measured using a validated, automated oscillometric monitor in triplicate.Results. Twenty‑three healthy subjects were enrolled (16 female; mean age 21.3 ± 1.6 years; body mass index 20.6 ± 2.4 kg/m2). The diastolic blood pressure (DBP) was lower in vitamin K‑deficient subjects (58 ± 9 vs. 67 ± 5 mmHg, p = 0.01). The mean arterial blood pressure also differed (75 ± 9 vs. 83 ± 6, p = 0.02). PIVKA‑II levels correlated with DBP only (Pearson’s R = -0.41, p &lt; 0.05; Spearman’s ρ ns.). Stepwise regression identified PIVKA‑II concentrations as the only independent parameter associated with DBP (adjusted R2 = 13.1%; PIVKA‑II: β = -0.41; 95%CI -1.87-(-0.00098), t = -2.08, p &lt; 0.05).Conclusions. The relationship between vitamin K deficiency and low DBP in young adults should be investigated further.

Lower diastolic blood pressure in healthy subjects with vitamin K deficiency: a preliminary cross-sectional study

Introduction. There is a growing body of evidence for the role of vitamin K in cardiovascular health. As a cofactor of carboxylation of the matrix Gla protein it prevents arterial calcification. However, the data on the relationship between vitamin K status and the blood pressure are scarce, and particularly so in persons without the burden of cardiovascular risk factors. Material and Methods. We performed a pilot cross-sectional study, in which we hypothesized that vitamin K deficiency is associated with a higher blood pressure in young, healthy people. The concentration of protein induced by vitamin K absence-II (PIVKA-II) larger than 2 ng/mL was chosen as a proxy for vitamin K deficiency; it was assessed in serum using ELISA. Blood pressure was measured using a validated, automated oscillometric monitor in triplicate.Results. Twenty-three healthy subjects were enrolled (16 female; mean age 21.3 ± 1.6 years; body mass index 20.6 ± 2.4 kg/m2). The diastolic blood pressure (DBP) was lower in vitamin K-deficient subjects (58 ± 9 vs. 67 ± 5 mmHg, p = 0.01). The mean arterial blood pressure also differed (75 ± 9 vs. 83 ± 6, p = 0.02). PIVKA-II levels correlated with DBP only (Pearson’s R = -0.41, p &lt; 0.05; Spearman’s ? ns.). Stepwise regression identified PIVKA-II concentrations as the only independent parameter associated with DBP (adjusted R2 = 13.1%; PIVKA-II: ß = -0.41; 95%CI -1.87-(-0.00098), t = -2.08, p &lt; 0.05).Conclusions. The relationship between vitamin K deficiency and low DBP in young adults should be investigated further.

Biological Systems of Vitamin K: A Plasma Nutriproteomics Study of Subclinical Vitamin K Deficiency in 500 Nepalese Children.

Vitamin K (VK) is a fat-soluble vitamin whose deficiency disrupts coagulation and may disturb bone and cardiovascular health. However, the scale and systems affected by VK deficiency in pediatric populations remains unclear. We conducted a study of the plasma proteome of 500 Nepalese children 6–8 years of age (male/female ratio = 0.99) to identify proteins associated with VK status. We measured the concentrations of plasma lipids and protein induced by VK absence-II (PIVKA-II) and correlated relative abundance of proteins quantified by mass spectrometry with PIVKA-II. VK deficiency (PIVKA-II >2 μg/L) was associated with a higher abundance of low-density lipoproteins, total cholesterol, and triglyceride concentrations (p < 0.01). Among 978 proteins observed in >10% of the children, five proteins were associated with PIVKA-II and seven proteins were differentially abundant between VK deficient versus sufficient children, including coagulation factor-II, hemoglobin, and vascular endothelial cadherin, passing a false discovery rate (FDR) threshold of 10% (q < 0.10). Among 27 proteins associated with PIVKA-II or VK deficiency at a less stringent FDR (q < 0.20), a network comprised of hemoglobin subunits and erythrocyte anti-oxidative enzymes were highly and positively correlated each other (all r > 0.7). Untargeted proteomics offers a novel systems approach to elucidating biological processes of coagulation, vascularization, and erythrocyte oxidative stress related to VK status. The results may help elucidate subclinical metabolic disturbances related to VK deficiency in populations.

Presence of a hypovascular hepatic nodule showing hypointensity on hepatocyte‐phase image is a risk factor for hypervascular hepatocellular carcinoma

To determine whether the presence of a hypovascular nodule in the liver showing hypointensity on hepatocyte-phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) is a risk factor for hypervascular hepatocellular carcinoma (HCC) in patients with chronic liver disease. Forty-one patients with pathologically confirmed hypervascular HCC and 41 age- and gender-matched controls were retrospectively selected. These patients had undergone EOB-MRI at least twice: the latest EOB-MRI and EOB-MRI performed more than 6 months earlier. History of hypervascular HCC, presence of a hypointense hypovascular nodule in previous hepatocyte-phase MR images, percent prothrombin time, platelet count, serum levels of albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, α-fetoprotein, and protein induced by vitamin K absence-II (PIVKA-II) were variables evaluated by multivariate logistic regression analysis. Multivariate analysis revealed that serum albumin level (odds ratio [95% confidence interval], 0.19 [0.06-0.57]; P = 0.0024), history of hypervascular HCC (8.62 [2.71-32.8]; P = 0.0001), and presence of a hypointense hypovascular nodule (4.18 [1.18-17.2]; P = 0.0256) were significant risk factors for hypervascular HCC. Patients with chronic liver disease showing a hypointense hypovascular nodule in the liver on hepatocyte-phase EOB-MRI have a high risk of HCC development.

Vitamin K Deficiency due to Prolongation of Antibiotic Treatment and Decrease in Food Intake in a Catatonia Patient

Vitamin K is a factor of the enzyme that is in charge of -carboxylation of glutamic acid. It is a fat-soluble vitamin that occurs naturally in plants (vitamin K1) and is produced by gram-negative bacteria in the human gastrointestinal tract (vitamin K2). Prolongation of prothrombin time (PT), bleeding tendency, and protein induced by vitamin K absence-II (PIVKA-II) develop due to obstructive jaundice, diarrhea, or long use of antibiotics. We evaluated a patient with catatonia and vitamin K deficiency associated with prolonged antibiotic treatment and a decrease in food intake.

Preoperative Radiologic and Postoperative Pathologic Risk Factors for Early Intra-Hepatic Recurrence in Hepatocellular Carcinoma Patients Who Underwent Curative Resection

PurposeThe risk of hepatocellular carcinoma (HCC) recurrence must be considered ahead of surgery. This study was undertaken to identify pre-operative risk factors for early intrahepatic recurrence of HCC after curative resection in a large-scale.Materials and MethodsWe retrospectively reviewed the preoperative three-phase multi-detector CT (MDCT) and laboratory data for 240 HCC patients who underwent curative resection; tumor size, number, gross shape, capsule integrity, distinctiveness of tumor margin, portal vein thrombosis (PVT), alpha-fetoprotein level (AFP), and protein induced by vitamin K absence-II (PIVKA-II) levels were assessed. Surgical pathology was reviewed; tumor differentiation, capsule, necrosis, and micro-vessel invasion were recorded.ResultsHCC recurred in 61 patients within six months (early recurrence group), but not in 179 patients (control group). In univariate analysis, large tumor size (p = 0.018), shape (p = 0.028), poor capsule integrity (p = 0.046), elevated AFP (p = 0.015), and PIVKA-II (p = 0.008) were significant preoperative risk factors. Among the pathologic features, PVT (p = 0.023), Glisson's capsule penetration (p = 0.033), microvascular invasion (p < 0.001), and poor differentiation (p = 0.001) showed statistical significance. In multivariate analysis, only the histopathologic parameters of microvascular invasion and poor differentiation achieved statistical significance.ConclusionPreoperative CT and laboratory parameters showed limited value, while the presence of microscopic vascular tumor invasion and poorly differentiated HCC correlated with higher risk of early recurrence after curative resection.

Successful treatment of multiple lung metastases of hepatocellular carcinoma by combined chemotherapy with docetaxel, cisplatin and tegafur/uracil

We report the successful treatment of multiple lung metastases after hepatic resection for hepatocellular carcinoma (HCC) with combined docetaxel, cisplatin (CDDP), and enteric-coated tegafur/uracil (UFT-E). A 68-year-old man was diagnosed with multiple lung metastases of HCC 7 mo after partial hepatectomy for HCC. Oral UFT-E was given daily and docetaxel and CDDP were given intra-arterially (administered just before the bronchial arteries) every 2 wk via a subcutaneous injection port. One month after starting chemotherapy, levels of tumor marker, protein induced by vitamin K absence II (PIVKA-II), decreased rapidly, and after a further month, chest X-ray and computed tomography revealed the complete disappearance of multiple liver metastases. Two years after the combined chemotherapy, HCC recurred in the liver and was treated but no pulmonary recurrence occurred. In the absence of a standardized highly effective therapy, this combined chemotherapy with docetaxel, CDDP and UFT-E may be an attractive option for multiple lung metastases of HCC.

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.

Vitamin K status in cystic fibrosis.

Appearance of PIVKA-II (protein induced by vitamin K absence-II) in serum is a biochemical sign of insufficient vitamin K-dependent carboxylation of prothrombin. Plasma concentrations of PIVKA-II and vitamin K1 were determined in 24 children with cystic fibrosis. Eight were supplemented with vitamin K1. The purpose of the study was to determine the occurrence of vitamin K deficiency in cystic fibrosis and to evaluate the effect of vitamin K supplementation. PIVKA-II was detectable in only one unsupplemented child. In this patient, the concentration of vitamin K1 was below the limit of detection of 60 ng/l. Vitamin K1 levels in the other unsupplemented children were normal (mean 476 ng/l = 1 mmol/l). The supplemented patients showed extremely high levels of vitamin K1 (mean 22445 ng/l = 50 nmol/l). In conclusion, vitamin K deficiency occurs infrequently in cystic fibrosis. Checking the coagulation system is advised, but routine vitamin K supplementation is not recommended. If additional vitamin K is needed, the starting dose should not exceed 1 mg daily.

Maternal-fetal transport of vitamin K 1 and its effects on coagulation in premature infants

We conducted a prospective study to determine (1) the maternal-fetal vitamin K1 transport in premature infants after vitamin K1 was given to the mothers antenatally and (2) the vitamin K1 effects on blood coagulation in the babies. Women in labor at less than or equal to 34 weeks of gestation were randomly selected to receive antenatal vitamin K1, 5 mg given intramuscularly (vitamin K1 group), or no vitamin K1 (control group). Eight infants, including one set of twins, were in the vitamin K1 group and six in the control group. Vitamin K1 concentrations were higher in the vitamin K1 group than in the control group (p = 0.06). Activated partial thromboplastin time was prolonged, and factor II coagulation activity and factor II antigen were proportionately decreased in cord plasma in both groups. The average ratio of factor II coagulation activity to antigen was not decreased in either group. Protein induced by vitamin K absence-II (PIVKA-II) was not detectable in any cord plasma sample in either group. These findings support previous reports that the decreased vitamin K-dependent coagulation activity in premature infants is the result of reduced synthesis of precursor proteins, rather than the result of vitamin K deficiency, and suggest that additional vitamin K1 is not likely to improve coagulation activity. Among those infants who underwent cranial ultrasonography, all four in the vitamin K1 group and one of five in the control group had mild intraventricular hemorrhage. Studies of a larger number of patients are necessary before it can be established that maternal antenatal administration of vitamin K1 results in improvement of coagulation and the prevention of intraventricular hemorrhage in premature infants.