Clinical evaluation of plasma des-γ-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes

We measured des--carboxyprothrombin (DCP) (prothrombin induced by vitamin K absence or antagonist-II, abbreviated as PIVKA-II) by a newly developed enzyme immunoassay using an anti-DCP monoclonal antibody in 665 human subjects, of which 112 were patients with hepatocellular carcinoma (HCC). PIVKA-II was elevated to more than 0.1 AU/ml in 54 of the 112 patients (48.2%) with HCC, while it was positive only in 7.1% of those with liver cirrhosis and 3.1% of those with chronic hepatitis. Three patients with elevated PIVKA-II greater than 0.1 AU/ml who had been diagnosed as having liver cirrhosis by ultrasonography and computed tomography at the start of this study developed a diffuse type of HCC three or six months later, which was detected by angiography. No obvious correlation was observed between plasma PIVKA-II concentration and serum -fetoprotein (AFP) level in HCC patients. Of the 112 HCC patients, 40.2% showed an increase in AFP to above 200 ng/ml. In the remaining patients, 32.8% had a PIVKA-II concentration greater than 0.1 AU/ml. In these patients with a negative or low serum AFP concentration, PIVKA-II proved to be a valuable tumor marker for laboratory diagnosis of HCC. Among them, 59.8% tested positive for PIVKA-II and/or AFP. Thus, combination assay with PIVKA-II and AFP seems useful for increasing the accuracy of laboratory diagnosis of HCC. None of patients with a solitary tumor smaller than 2 cm had elevated PIVKA-II. In patients with larger-sized and multiple HCC, positive results of elevated PIVKA-II were more frequent than those of increased AFP. Thus, the determination of PIVKA-II may be more useful than AFP assay in patients with larger-sized and multiple tumors. The levels of plasma PIVKA-II concentration were higher in patients with larger-sized and multiple tumors than in those with smaller ones. In 20 patients, PIVKA-II decreased significantly after transcatheter arterial embolization (TAE) therapy, and in eight of these 20 patients it normalized after TAE. In conclusion, plasma PIVKA-II might be used as a valuable marker for the diagnosis and screening of HCC, especially in patients with negative or low AFP and in those with larger-sized and multiple tumors. However, its usefulness for mass screening of small HCC is limited.     

Sensitive measurement of serum abnormal prothrombin (PIVKA-II) as a marker of hepatocellular carcinoma.

BACKGROUND/AIMS: The usefulness of abnormal prothrombin (PIVKA-II) for diagnosis of small HCC has been limited by its low sensitivity, despite a high specificity. METHODOLOGY: The serum concentration of PIVKA-II was determined by using a new sensitive enzyme immunoassay (EIA) kit in patients with hepatocellular carcinoma (HCC), liver cirrhosis (LC), or chronic hepatitis (CH) and normal controls (NC). alpha-Fetoprotein (AFP) was simultaneously determined in same patients. RESULTS: This kit has made it possible to detect low concentrations of PIVKA-II in the NC. The serum PIVKA-II concentration (mean +/- SE) was 15.7 +/- 1.1 mAu/ml, 16.1 +/- 2.0 mAu/ml, 26.3 +/- 7.2 mAu/ml and 5420.3 +/- 3960.0 mAu/ml in NC, CH, LC and HCC, respectively. Among 106 patients with HCC, 74 patients (69.8%) were positive for PIVKA-II (> or = 40 mAu/ml), while only 9 patients out of 68 patients with LC were positive (13.2%) and only 2 out of 90 patients with CH were positive (2.2%). No significant correlation was observed between AFP and PIVKA-II levels. With combined assay of AFP and PIVKA-II, the positive rate for HCC was increased to 78.3%. Among 14 patients with HCC < 20 mm in diameter. 7 were positive for PIVKA-II, and 6 out of 10 patients with HCC between 20 and 30 mm in diameter were positive for PIVKA-II. There was a correlation between tumor size and the PIVKA-II level. CONCLUSIONS: Determination of PIVKA-II by this new EIA kit could be useful for the diagnosis of HCC, especially combined with determination of AFP.     

Clinical evaluation of plasma abnormal prothrombin (PIVKA-II) in patients with hepatocellular carcinoma

The clinical usefulness of plasma abnormal prothrombin, defined as a protein induced by vitamin K absence or antagonist-II: PIVKA-II, as a tumor marker for hepatocellular carcinoma (HCC), was evaluated. Plasma PIVKA-II concentration was determined by an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody specific for PIVKA-II. Forty-one (65%) out of 63 patients with HCC had an abnormal PIVKA-II level above 0.13 arbitrary units (AU)/ml; the level was above 0.3 AU/ml in 33 patients (52%) and above 0.5 AU/ml in 27 patients (43%). On the other hand, most of the 282 patients with various liver diseases other than HCC had normal or slightly elevated levels of PIVKA-II. Their values were all below 0.5 AU/ml, with the exception of 2 patients with decompensated liver cirrhosis. The patients with PIVKA-II values above 0.5 AU/ml were strongly suspected of having HCC. Plasma PIVKA-II levels were not related to serum alpha-fetoprotein (AFP) levels, but were above 0.5 AU/ml in 14 (44%) out of the 32 patients whose serum AFP levels were below 400 ng/ml. In some patients with HCC, PIVKA-II was increased throughout the course of the disease, and in others it normalized after surgical resection of the tumor. We conclude that the plasma PIVKA-II assay by the ELISA method using a monoclonal antibody is a useful diagnostic tool for monitoring HCC, particularly in HCC patients with low AFP levels.     

Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group

OBJECTIVE: We evaluated the measurements of serum alpha-fetoprotein (AFP) and the protein induced by vitamin K absence (PIVKA-II) in 734 patients with chronic hepatitis (CH) and liver cirrhosis (LC) who had been followed-up for the development of hepatocellular carcinoma (HCC). METHODS: Serum AFP and PIVKA-II were measured every month and abdominal ultrasonography was performed every 3 months. Youden's index (sensitivity + specificity -1) was calculated. RESULTS: On an average follow-up period of 374.5 days, HCC was detected in three HBsAg-positive LC patients (10.0%/yr), four anti-HCV-positive CH patients (1.35%/yr), 21 anti-HCV-positive LC patients (7.8%/yr), and one patient with both HBsAg- and anti-HCV-positive LC (22.7%/yr). At the time of HCC detection, the size of HCC was 4.7+/-0.6 (mean +/- SD) cm in HBsAg-positive patients and 2.4+/-1.3 cm in anti-HCV-positive patents. Cut-off values of 20 ng/ml for AFP (Youden's index = 0.422) and 60 mAU/ml for PIVKA-II (Youden's index = 0.316) gave the highest index for each marker. When these two markers were combined, cut-off values of 40 ng/ml for AFP and 80 mAU/ml for PIVKA-II gave the highest index (Youden's index = 0.500, sensitivity = 65.5%, specificity = 85.5%, positive predictable value = 14.8%, negative predictable value = 98.3%). The levels of AFP or PIVKA-II increased within three months before the detection of HCC. CONCLUSIONS: Simultaneous measurements of serum AFP and PIVKA-II levels that are performed every 3 months are useful for detecting a developing HCC. The optimal cut-off values for AFP and PIVKA-II may be 40 ng/ml and 80 mAU/ml, respectively.     

Clinical usefulness of des-γ-carboxy prothrombin assay in early diagnosis of hepatocellular carcinoma

Des--carboxy prothrombin (DCP) was evaluated as a serological marker for hepatocellular carcinoma (HCC), particularly in patients with early HCC. In 1192 patients with various diseases, plasma DCP levels were measured by a newly developed enzyme immunoassay method using an anti-DCP monoclonal antibody. Of the 254 patients with HCC, 143 (56%) had abnormal DCP levels of greater than 0.1 AU/ml. In contrast, elevated DCP levels were rarely observed in patients with chronic hepatitis, liver cirrhosis, metastatic liver cancer, and other malignant tumors. Because no correlation was observed between DCP and -fetoprotein (AFP), the combined measurement of these two complementary markers appears to be useful in the diagnosis of HCC. Since normal levels were observed in 29 of 30 patients (97%) with small liver tumors measuring 2 cm or less in diameter, the diagnostic application of the DCP assay to small liver tumors is limited. However, in patients with tumors larger than 2 cm, the plasma DCP assay may even be more useful than AFP. Among 46 patients with liver cirrhosis or chronic hepatitis who subsequently developed HCC, significantly increased DCP and AFP levels were observed in nine patients (20%) and 14 patients (30%), respectively, when a tumor was detected. When the results of both assays were combined, 19 patients (41%) had elevated levels of one or both markers. Although the plasma DCP assay alone is not sensitive enough to detect early small liver cancers, it could be applied as a complementary tumor marker together with AFP. The use of both these markers together with imaging modalities in the regular follow-up of patients with chronic liver disease who are at high risk for HCC might be of great benefit.This work was supported in part by a grant from the Japanese Society of Hepatology.     

Meshwork pattern is an important risk factor for development of hepatocellular carcinoma in patients with HBV-related chronic hepatitis and cirrhosis

We analyzed the importance of ‘meshwork pattern’, a sign representing severe irregularity on the intra-hepatic echogram, in hepatitis B virus (HBV)-related chronic hepatitis and cirrhosis, as a risk factor for development of hepatocellular carcinoma (HCC). Two hundred and thirty-one patients (143 men and 88 women) with HBV-related chronic hepatitis and cirrhosis who visited our hospital from January 1993 to December 1994 were enrolled in this study. Since enrollment, abdominal ultrasonography had in principle been performed every 3 months for cirrhotic patients and every 4–6 months for patients with chronic hepatitis for HCC screening. Cumulative HCC incidences in patient groups positive or negative for meshwork pattern were calculated by the Kaplan–Meier method. The incidence of HCC was significantly higher in the group positive for meshwork pattern (average incidence per year: 4.4%) than in the group negative for it (average incidence per year: 0.5%) (P<0.0001, Mantel–Cox test). On regression analysis with Cox's proportional hazards model, sex, α-fetoprotein and meshwork pattern were selected as independent risk factors for HCC. In conclusion, meshwork pattern appears to be an ultrasonographic sign useful for detecting a latent risk factor for HCC in patients with HBV-related chronic hepatitis and cirrhosis.     

Hepatocellular Carcinoma Associated with AlcoholicLiver Disease: A Clinicopathological Study and Genetic Polymorphism of Aldehyde Dehydrogenase 2

In this paper, we describe a clinicopathological study of primary hepatocellular carcinoma (HCC) associated with alcoholic liver disease without hepatitis virus infection. In 180 HCC patients who were admitted to Asahikawa Medical College Hospital from 1987 to 1995, 10 patients (6%) had HCC associated with pure alcoholic liver disease (AI-HCC), whereas the HCC in 165 patients was associated with chronic viral liver diseases, in 2 with primary biliary cirrhosis, in 1 each with coexistence of the hepatitis C virus infection and hemochromatosis, and in 2 with cirrhosis of unknown origin. In the AI-HCC group, all patients were male. The diagnosis of HCC was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Four cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in three cases and liver cirrhosis in seven cases. HCC was diagnosed histologically in all cases. Serum α-fetoprotein and PIVKA-II were positive in patients with advanced HCC. In cases with small HCC, the tumor was resected surgically in three cases and percutaneous ethanol injection was performed in two cases. In four cases with small HCC, the patients were alive without tumor recurrence during the observation period. In advanced HCC, transcatheter arterial chemolipiodolization was performed. In the analysis of genetic polymorphism of ALDH 2, all AI-HCC had ALDH 2¹/2¹.     

Role of serum prothrombin induced by vitamin K absence or antagonist-II in the early detection of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

Objective. The role of serum prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) in the early detection of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection has not yet been clearly identified. The purpose of the study was to evaluate the sensitivity and specificity of PIVKA-II, alone or in combination with alpha-fetoprotein (AFP), for the detection of HCC during surveillance, and to determine whether PIVKA-II was a significant risk factor for patient survival. Material and methods. During surveillance, 106 HCC cases and 100 non-HCC cases of chronic HBV infection were included. Sensitivity and specificity of AFP and PIVKA-II were obtained through cut-off values of 20 ng/ml and 40 mAU/ml, respectively. The Cox proportional hazards model was used to determine whether PIVKA-II would be a significant risk factor for patient survival. Results. The sensitivity rates of AFP and PIVKA-II were 57.5% (61/106) and 51.9% (55/106), respectively. Of 45 patients negative for AFP, 22 were positive for PIVKA-II. A combination of AFP and PIVKA-II increased the sensitivity to 78.3% (83/106). The specificities of AFP and PIVKA-II were 88.0% and 97.0%, respectively. PIVKA-II was not a significant risk factor for patient survival after multivariate analysis. Conclusions. PIVKA-II can be used as a tumor marker for the early detection of HCC in patients with chronic HBV infection, especially in combination with AFP.     

Clinical evaluation of serum tissue inhibitor of metalloproteinases-1 levels in patients with liver diseases

Serum levels of the tissue inhibitor of metalloproteinases-1 (TIMP-1) were measured in 268 patients with liver diseases by means of a one-step sandwich enzyme immunoassay. In the cases of acute hepatitis, chronic active hepatitis (CAH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC), the levels of TIMP-1 were higher than those of the control group. Tissue inhibitor of metalloproteinases-1 levels correlated with type III procollagen peptide and with type IV collagen, indicating TIMP-1 as a useful marker for hepatic fibrosis. Levels of TIMP-1 also correlated with aspartate aminotransserase and alanine aminotransferase levels and showed the highest levels in acute hepatitis. Thus, TIMP-1 might also reflect hepatic inflammation. Serum levels of α-fetoprotein and TIMP-1 had a significant positive correlation in patients with HCC. A cut-off level of TIMP-1 between LC and HCC was set at 440 ng/mL, having a low sensitivity and a high specificity. These results suggest the usefulness of TIMP-1 as a tumour marker in cases of HCC where α-fetoprotein levels are not elevated.     

α-fetoprotein and p53 autoantibodies in patients with chronic hepatitis C

Hepatitis C virus infection is a common cause of chronic liver disease and hepatocellular carcinoma. Recently, mutations in the p53 tumor suppressor gene with generation of circulating autoantibodies to p53 protein have been detected in a significant proportion of patients with different malignancies. Using ELISA methods we assessed α-fetoprotein and anti-p53 as serological screening parameters for hepatocellular carcinoma in 147 consecutive patients with chronic hepatitis C. Liver cirrhosis was histologically diagnosed in 58 patients (39.5%) and a hepatocellular carcinoma confirmed in seven patients (4.8%). Serum α-fetoprotein was raised above 20 ng/ml in 26/147 patients and above 100 ng/ml in 5/147 patients. In 6/7 patients with hepatocellular carcinoma, α-fetoprotein was raised above 20 ng/ml, but only in 3/7 cases above 100 ng/ml, resulting in a sensitivity and specificity of 85.7% and 85.7% (α-fetoprotein>20 ng/ml) and 42.9% and 98.6% (α-fetoprotein>100 ng/ml), for the detection of hepatocellular carcinoma, respectively. Autoantibodies to p53 were detected in 3/7 patients with hepatocellular carcinoma, but in 0/140 patients without malignancy (sensitivity 42.9%, specificity 100%). Screening for hepatocellular carcinoma was improved by combining α-fetoprotein measurement (level>100 ng/ml) with detection for anti-p53 (sensitivity 71.4%, specificity 98.6%). In conclusion, the presence of anti-p53 was highly specific for malignancy and independent of α-fetoprotein status. Further studies including a larger number of patients with hepatitis C virus-related hepatocellular carcinoma are required to investigate whether serological testing for anti-p53 in combination with α-fetoprotein might improve the detection of hepatocellular carcinoma in high-risk patients with liver cirrhosis.     

Usefulness of ED036 kit for measuring serum PIVKA-II levels in small hepatocellular carcinoma

As a tumor marker for hepatocellular carcinoma (HCC), serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) has high specificity, yet its sensitivity is relatively low, making it less suitable to serve as an adjunct in the diagnosis of small HCC, Recently, the ED036 kit (Eisai, Tokyo, Japan), whose detection limit is approximately ten times superior to that of a conventional kit (Eitest MONOP II, Eisai) has been developed. In this study, serum PIVKA-II levels in serum samples from 83 patients with benign chronic liver diseases (CLD) and 129 patients with HCC were measured with these two kits. With the ED036 kit, the cut-off value was set at 40 mAU/ml. For PIVKA-II measured with the ED036 kit, sensitivity was 45.0%, specificity 92.8%, and accuracy 63.7%, when we discriminated patients with HCC from those with CLD without HCC. While maintaining a high specificity, of 92.8%, the ED036 kit showed a significantly higher sensitivity than the conventional kit (45.0% versus 27.9%;P<0.0001). With patients who had HCC consisting of a single nodule 30mm or less in diameter, the positivity rate for serum PIVKA-II with the ED036 kit was significantly greater than the rate with the conventional kit (21.4% versus 9.5%;P<0.005). Thus, the ED036 kit was thought to be more useful than the conventional kit as a tumor marker for small HCC.     

Plasma abnormal prothrombin (PIVKA-π): A new and reliable marker for the detection of hepatocellular carcinoma

We evaluated the clinical usefulness of a protein induced by vitamin K absence, antagonist-prothrombin (PIVKA-II), in detecting hepatocellular carcinoma (HCC) specifically in patients with liver cirrhosis, and the possible correlation between levels of PIVKA-II and pathological features of HCC. Plasma levels of PIVKA-II and alpha-fetoprotein (AFP) were measured in 628 patients with various diseases, including 253 with liver cirrhosis and 116 with HCC. PIVKA-II was detected (greater than or equal to 0.1 arbitrary unit/mL) in 54.3% of HCC and the concentration showed a positive correlation with the tumour size. As a screening test for the detection of HCC, PIVKA-II produced values comparable with those of AFP with a sensitivity, specificity and validity of 52.8, 98.8 and 51.6% respectively. Sixteen of 45 patients (37%) with HCC who had low AFP (less than 100 ng/mL) levels were positive for PIVKA-II. No apparent relationship, however, could be found between the levels of PIVKA-II and the aetiology or pathological findings of HCC. These results suggest that PIVKA-II can be a reliable marker for detecting HCC in patients with liver cirrhosis.     

Abnormal prothrombin: Evaluation as a tumour marker and localization in tissues of patients with hepatocellular carcinoma

Abstract In this study, the diagnostic significance of PIVKA-II concentrations in various liver diseases was evaluated, and the use of PIVKA-II as a tumour marker for hepatocellular carcinoma (HCC) was discussed. Also, the location of abnormal prothrombin (PIVKA-II) production in HCC by indirect immunoperoxidase staining was examined. There was a good correlation between plasma and serum PIVKA-II concentrations, indicating that serum samples are adequate for PIVKA-II measurements. Fifty-four of 97 (55.7%) patients with HCC, one of 10 (10%) patients with metastatic liver cancer and two of 47 (4.3%) patients with liver cirrhosis had positive serum PIVKA-II concentrations. Positive serum PIVKA-II concentrations were found more frequently in patients with HCC than in any other liver disease (P < 0.01). Of the 97 patients with HCC, 54 (55.7%) were PIVKA-II positive, 76.3% had serum concentrations of either PIVKA-II or α-fetoprotein, indicating the usefulness of both tumour markers in the diagnosis of HCC.
Using frozen sections of tissue specimens obtained at autopsy or during surgery, the localization of PIVKA-II was examined by indirect immunoperoxidase staining with specific anti-PIVKA-II antibodies. Tissues from 12 of 22 patients with HCC had positive PIVKA-II indirect immunoperoxidase staining only in the cancer cells. Cells with greater atypia tended to have stronger cytoplasmic staining. No specific staining was observed in non-cancerous cells.
These findings suggest that PIVKA-II is synthesized specifically in hepatic cancer cells.     

Diagnostic value of AFP-L3 and PIVKA-Ⅱin hepatocellular carcinoma according to total-AFP

AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC surveillance were included in this study.Of the 168 patients,90(53.6%)had HCC including newly developed HCC(n=82)or recurrent HCC after treatment(n=8).Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment.HCC was diagnosed by histological examination,appropriate imaging characteristics-computed tomography or magnetic resonance imaging.Control sera were collected from 78 patients with benign liver disease(BLD),which were obtained during routine surveillance with a suspicion of HCC.AFP,AFP-L3 and PIVKA-Ⅱwere measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer.The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP<20 ng/mL. RESULTS:Of 90 HCC patients,38(42.2%)patients had AFP<20 ng/mL,20(22.2%)patients had AFP 20-200 ng/mL and 32(35.6%)patients had AFP>200 ng/mL.Of the 78 BLD patients,74(94.9%)patients had AFP<20 ng/mL.After adjustment for age and HBV infection status,AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels(<20 ng/mL)(P<0.001).In a total of 168 patients,areas under the curve(AUC)for HCC were 0.879,0.887,0.801 and 0.939 for AFP,AFP-L3,PIVKA-Ⅱand the combined markers,respectively.The combined AUC for three markers showed higher value than the AUCs of individual marker(P<0.05).AFP-L3 had higher AUC value than PIVKA-Ⅱfor HCC detection in entire patients(P =0.043).With combination of AFP-L3(cut-off>5%) and PIVKA-Ⅱ(cut-off>40 AU/L),the sensitivity were 94.4%and specificity were 75.6%in all patients.In 112 patients with lo     

Diagnostic value of PIVKA-Ⅱ and alpha-fetoprotein in hepatitis B virus-associated hepatocellular carcinoma

AIM: To determine the cutoff values and to compare the diagnostic role of alpha-fetoprotein(AFP) and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ) in chronic hepatitis B(CHB).METHODS: A total of 1255 patients with CHB, including 157 patients with hepatocellular carcinoma(HCC), 879 with non-cirrhotic CHB and 219 with cirrhosis without HCC, were retrospectively enrolled. The areas under the receiver operating characteristic(AUROC) curves of PIVKA-Ⅱ, AFP and their combination were calculated and compared.RESULTS: The optimal cutoff values for PIVKA-Ⅱ and AFP were 40 m AU/m L and 10 ng/m L, respectively, for the differentiation of HCC from nonmalignant CHB. The sensitivity and specificity were 73.9% and 89.7%, respectively, for PIVKA-Ⅱ and 67.5% and 90.3% for AFP, respectively. The AUROC curves of both PIVKA-Ⅱ and AFP were not significantly different(0.854 vs 0.853, P = 0.965) for the differentiation of HCC from nonmalignant CHB, whereas the AUROC of PIVKA-Ⅱ was significantly better than that of AFP in patients with cirrhosis(0.870 vs 0.812, P = 0.042). When PIVKA-Ⅱ and AFP were combined, the diagnostic power improved significantly compared to either AFP or PIVKA-Ⅱ alone for the differentiation of HCC from nonmalignant CHB(P 0.05), especially when cirrhosis was present(P 0.05).CONCLUSION: Serum PIVKA-Ⅱ might be a better tumor marker than AFP, and its combination with AFP may enhance the early detection of HCC in patients with CHB.     

The diagnostic value of the assay of des-gamma-carboxy prothrombin in the detection of small hepatocellular carcinoma.

Des-gamma-carboxy prothrombin (DCP) assay was performed by a staphylocoagulase method in 35 consecutive patients with small (less than 5 cm), resectable hepatocellular carcinoma (HCC). They also simultaneously received serum alpha-fetoprotein (AFP) assay. According to diagnostic strategy, patients were divided into two groups. Group I consisted of eight patients who were candidates for a mass screening project for HCC with elevated AFP levels (greater than 20 ng/ml). Five of these patients had an increased DCP level (greater than 6 U/l). Group II included 27 victims of chronic hepatitis B or cirrhosis whose tumors were detected by ultrasonography during regular follow-up. In this group, increased DCP and AFP levels were observed in 11 and 16 cases, respectively. Of 14 patients with smaller HCC (less than 3 cm), only three had elevated DCP levels, while eight patients had an abnormal AFP level. When these two assays were combined, 18 of 27 patients in group II and nine of 14 patients with smaller HCC (less than 3 cm) revealed elevation of one or both of the two markers. A total of 16 out of 35 patients with small HCC had abnormal DCP levels. In conclusion, DCP assay is less sensitive than AFP assay in the detection of small HCC, and the combination of both markers has little complementary effect.     

Plasma Abnormal Prothrombin Levels in Patients with Small Hepatocellular Carcinoma

The diagnostic value of plasma abnormal prothrombin (PIVKA-II) measurements in detecting relatively small hepatocellular carcinomas (HCC), less than 5 cm in diameter, was compared with that of serum α-feto-protein (AFP) determinations. Among 18 patients with relatively small hepatocellular carcinoma (HCC), abnormal PIVKA-II values were found in only three (16.6%). Highly elevated serum AFP levels (>200 ng/ ml) relatively specific for HCC were seen also in three patients. However, nonspecific elevation of PIVKA-II in patients with liver cirrhosis not accompanied by HCC was much less than that of AFP. Although complementary, both tests appear to be of limited value in early detection of HCC, indicating that searches for other markers are necessary, to allow early detection of small HCC.     

Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis

A rare case of hepatocellular carcinoma (HCC) in a 78-year-old woman with a 10-year history of autoimmune hepatitis (AIH) without liver cirrhosis and no history of alcohol abuse, drug injection, or blood transfusion is presented. At the time HCC was diagnosed, based on imaging studies showing a 5-cm-diameter S6 liver tumor, she had normal liver function, positive anti-nuclear antibodies, negative hepatitis B and C markers, and elevated alfa-fetoprotein (AFP; 169 ng/ml) and protein-induced by vitamin K absence or antagonist II (PIVKA-II; 721 mAU/ml) levels. Following subsegmental S6 resection, no evidence of fibrosis or cirrhosis was observed.     

原发性肝癌患者外周血中甲胎蛋白mRNA的意义

目的由于ＰＣＲ技术的应用,血循环中癌细胞的检测近有很大进展．本文用ＲＴＰＣＲ检测肝癌（ＨＣＣ）和其他慢性肝病患者外周血中ＡＦＰｍＲＮＡ,藉以反映ＨＣＣ细胞的存在,并与其他血清标记物比较．方法ＨＣＣ患者２２例,肝硬变和慢性乙型肝炎患者各１０例,健康成人受试者（对照）５例．取患者和对照的外周血,分离单核细胞,提取总ＲＮＡ并作电泳鉴定,用合成的两对引物进行巢式ＲＴＰＣＲ扩增ＡＦＰｍＲＮＡ,同时分析血清ＡＦＰ和乙肝标记物．结果ＡＦＰｍＲＮＡ在１３例ＨＣＣ（５９１％）,２例肝硬变（２００％）患者外周血中测到,其余标本均为阴性．ＡＦＰｍＲＮＡ阳性的１３例患者肿瘤均大于５ｃｍ,为晚期患者．在该１３例患者中仅有６例（４６１％）在血清中测到ＡＦＰ,但有１２例（９２３％）ＨＢｓＡｇ,抗ＨＢｅ,抗ＨＢｃ全阳性,而ＡＦＰｍＲＮＡ阴性的５例该３标记物全阴性．结论ＲＴＰＣＲ扩增ＡＦＰｍＲＮＡ是检测ＨＣＣ和肝硬变患者循环肝癌细胞的敏感方法．患者外周血中的ＡＦＰｍＲＮＡ有可能作为肿瘤转移和复发的标记对ＨＣＣ诊断、随访观察和疗效评定有较大临床意义．     

Natural history of chronic hepatitis B REVEALed

Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to ≥1,000,000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B.