Carcinoma, Hepatocellular ; diagnosis ; pathology ; DNA ; blood ; DNA Methylation ; Humans ; Liver Neoplasms ; diagnosis ; pathology ; Polymerase Chain Reaction ; methods

OBJECTIVETo assess the value of detecting peripheral blood circulating tumor cells (CTCs) in the diagnosis and treatment of hepatocellular carcinoma (HCC).

METHODSA total of 296 patients diagnosed with HCC admitted in our department from July 2013 to January 2015 were analyzed, with 39 patients with benign liver disease serving as the control group. The distribution of CTCs in the peripheral blood of HCC patients were detected by CanPatrol(TM) CTCs, and its relationship with the clinical features and prognosis of the patients were analyzed.

RESULTSs CTCs were detected in 64.5% (191/296) of the HCC patients but in none of the control group (P<0.05). Positive CTCs in peripheral blood of HCC patients were significantly correlated with serum AFP level, tumor number, TNM stage, BCLC stage, portal vein tumor thrombus and metastasis (P<0.05). In 127 HCC patients receiving radical surgery, the patients positive for CTCs showed significantly shorter relapse-free survival time (P<0.05).

CONCLUSIONPositive CTCs in the peripheral blood may indicate a poor prognosis in HCC patients. CTCs may serve as a indicator for monitoring the prognosis of HCC.

Carcinoma, Hepatocellular ; blood ; diagnosis ; Case-Control Studies ; Humans ; Liver Neoplasms ; blood ; diagnosis ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Neoplastic Cells, Circulating ; Portal Vein ; pathology ; Prognosis

OBJECTIVETo investigate the dynamic expressions of TGF-beta 1 and TGF-beta 1 mRNA at different stages of hepatocellular carcinoma (HCC) development and their use in clinical diagnosis.

METHODSHepatoma models were developed with 2-FAA using male Sprague-Dawley (SD) rats. Morphological changes of the rat liver histological preparations (H and E stained) were studied. The fragment of TGF-beta 1 gene obtained was amplified by nested RT-PCR. Dynamic change of TGF-beta 1 level was quantitatively analyzed by ELISA. The distribution of TGF-beta 1 in the cells and its gene expression were detected in human HCC tissues.

RESULTSThe progressive increases of hepatic TGF-beta 1 and TGF-beta 1 mRNA were observed in rat hepatocytes which progressed from granular degeneration, atypical hyperplasia and finally to HCC development induced by 2-FAA. The expression levels in HCC tissues were significantly higher than those in the normal and degenerative ones. TGF-beta 1 was shown in rat hepatocytes by immunohistochemistry. Plasma TGF-beta 1 was detected in 89.5% of all the patients with HCC, but it was detected in 93.3% of them who had an AFP less than 400 microg/L. TGF-beta 1 mRNA showed a stronger expression in HCC tissues. TGF-beta 1 mRNA was found in peripheral blood mononuclear cells from all HCC patients with extrahepatic metastasis.

CONCLUSIONTGF-beta 1 may participate in hepatocyte canceration. The overexpression of TGF-beta 1 and TGF-beta 1 mRNA could be useful markers for early diagnosis and predicting prognosis of HCC.

Adult ; Aged ; Animals ; Biomarkers, Tumor ; blood ; Carcinoma, Hepatocellular ; blood ; diagnosis ; pathology ; Female ; Humans ; Liver Neoplasms, Experimental ; blood ; diagnosis ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; prevention & control ; Prognosis ; RNA, Messenger ; blood ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; blood

OBJECTIVEProtein induced by vitamin K absence or antagonist II (PIVKA II), also called des-gamma carboxy prothrombin (DCP), is a sensitive marker for the diagnosis of hepatocellular carcinoma (HCC), in Japan and the United States since the sensitive kits were available (1998). PIVKA II is not used in clinical diagnosis in China so far. The aim of this study was to assess the diagnostic value of PIVKA II in Chinese patients with HCC.

METHODSSerum PIVKA II and alpha-fetoprotein (AFP) levels were determined in 60 patients with HCC and 30 patients with cirrhosis not carrying HCC.

RESULTSThe mean serum concentration of PIVKA II in HCC patients (784.3 +/- 1364.1 mean +/- s) was higher than that in cirrhosis patients (16.1 +/- 31.7); this difference was highly significant (P < 0.0001). When the cutoff level of 40 mAU/ml was used as the level of discriminating HCC from cirrhosis, 51.7% of patients (31/60) with HCC had PIVKA II values above this level (sensitivity). Only 4 patients with cirrhosis had such high PIVKA II levels. Thus, the specificity of this test was 86.7% (26/30). Total accuracy was 62.2% [(31 + 26)/(60 + 30)]. Seven of 19 small HCCs (36.84%) had PIVKA II values above the cutoff level. Concentrations of AFP above 20 ng/ml were observed in 34 of 60 patients with HCC (56.7%) and in 11 patients with cirrhosis (36.7%). Eleven of 26 patients with HCC (46.2%) without increased AFP had concentrations of PIVKA II greater than 40 mAU/ml. No significant correlation was found between serum levels of AFP and PIVKA II that were measured in 60 HCC patients (rs = 0.101, P = 0.247). Combining the information from PIVKA II and AFP showed an increase of approximately 21.6% over AFP and 26.7% over PIVKA II alone. For small HCC patients, combining the information from PIVKA II and AFP showed an increase of approximately 15.8% over AFP alone and 21.1% over PIVKA II alone.

CONCLUSIONPIVKA II is a useful early diagnostic marker for HCC and may be more sensitive when combined with AFP in Chinese patients.

Adult ; Aged ; Aged, 80 and over ; Biomarkers ; Biomarkers, Tumor ; blood ; Carcinoma, Hepatocellular ; blood ; diagnosis ; pathology ; Female ; Humans ; Liver Cirrhosis ; blood ; Liver Neoplasms ; blood ; diagnosis ; pathology ; Male ; Middle Aged ; Protein Precursors ; blood ; Prothrombin ; alpha-Fetoproteins ; analysis

Recent studies have shown that circulating microRNAs are a potential biomarker in various types of malignancies. The aim of this study was to investigate the feasibility of using serum exosomal microRNAs as novel serological biomarkers for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We measured the serum exosomal microRNAs and serum circulating microRNAs in patients with CHB (n=20), liver cirrhosis (LC) (n=20) and HCC (n=20). Serum exosomal microRNA was extracted from 500 mul of serum using an Exosome RNA Isolation kit. The expression levels of microRNAs were quantified by real-time PCR. The expression levels of selected microRNAs were normalized to Caenorhabditis elegans microRNA (Cel-miR-39). The serum levels of exosomal miR-18a, miR-221, miR-222 and miR-224 were significantly higher in patients with HCC than those with CHB or LC (P<0.05). Further, the serum levels of exosomal miR-101, miR-106b, miR-122 and miR-195 were lower in patients with HCC than in patients with CHB (P=0.014, P<0.001, P<0.001 and P<0.001, respectively). There was no significant difference in the levels of miR-21 and miR-93 among the three groups. Additionally, the serum levels of circulating microRNAs showed a smaller difference between HCC and either CHB or LC. This study suggests that serum exosomal microRNAs may be used as novel serological biomarkers for HCC.
Adult ; Aged ; Biomarkers, Tumor/blood/genetics ; Carcinoma, Hepatocellular/blood/diagnosis/*genetics ; Exosomes/genetics ; Female ; Gene Expression Profiling ; Humans ; Liver/pathology ; Liver Neoplasms/blood/diagnosis/*genetics ; Male ; MicroRNAs/blood/*genetics ; Middle Aged

BACKGROUND/AIMS: Glypican-3 (GPC3) protein is highly expressed in hepatocellular carcinoma (HCC) tissue. It has been suggested as a diagnostic biomarker, but its inconsistent performance means that it requires further assessment. We therefore investigated the diagnostic value of the plasma GPC3 level compared to the alpha-fetoprotein (AFP) level as a diagnostic biomarker of HCC. METHODS: We enrolled 157 consecutive patients with newly diagnosed HCC and 156 patients with liver cirrhosis (LC) as the control group. GPC3 plasma levels were measured using two commercially available enzyme-linked immunosorbent assays (ELISAs, named as Assay 1 and 2), and AFP levels were measured using an enzyme-linked chemiluminescent immunoassay. The diagnostic accuracy was analyzed using the receiver operating characteristics (ROC) curve. RESULTS: Plasma GPC3 levels in HCC patients were very low (0–3.09 ng/mL) in Assay 1, while only 3 of the 157 patients (1.9%) showed detectable GPC3 levels in Assay 2. The median GPC3 level was not significantly elevated in the HCC group (0.80 ng/mL) compared with the LC group (0.60 ng/mL). The area under the ROC curve (AUC) for GPC3 was 0.559 in Assay 1. In contrast, the median AFP level was significantly higher in HCC (27.72 ng/mL) than in LC (4.74 ng/mL), with an AUC of 0.729. CONCLUSION: The plasma level of GPC3 is a poor diagnostic marker for HCC, being far inferior to AFP. The development of a consistent detection system for the blood level of GPC3 is warranted.
Aged ; Aged, 80 and over ; Area Under Curve ; Biomarkers, Tumor/blood ; Carcinoma, Hepatocellular/*diagnosis/pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Glypicans/*blood ; Humans ; Liver Neoplasms/*diagnosis/pathology ; Male ; Neoplasm Staging ; ROC Curve ; alpha-Fetoproteins/*analysis

BACKGROUND/AIMS: The extent of hepatic fibrosis is important in chronic liver disease. Liver biopsy is essential for diagnosis of fibrosis. However, biopsy is invasive and may not represent the whole liver state. Serum hyaluronic acid (HA), a major component of connective tissues, was introduced as a useful non-invasive index of hepatic fibrosis. The aim of this study was to evaluate the relationship among HA, the degree of fibrosis, several hematologic and biochemical parameters in patients with chronic liver diseases or post state liver transplantation (PSLT). METHODS: Total 102 cases were divided into 4 groups: 57 chronic hepatitis (CH), 12 cirrhosis, 21 hepatocellular carcinoma (HCC), 12 PSLT. HA was measured by enzyme-linked binding protein assay and evaluated in relation the degree of fibrosis, several hematologic and biochemical parameters. RESULTS: Among four groups, HCC showed the highest HA and HA of HCC significantly higher than that of CH. The degree of fibrosis were correlated with HA. HA was correlated with age, platelet count and albumin but, not with ALT and PT. There is no significant relation between HA and the presence of acute rejection in liver transplantation. CONCLUSIONS: In chronic liver diseases, HA is a useful non-invasive index of hepatic fibrosis and disease severity.
Adolescent ; Adult ; Aged ; Biological Markers/blood ; Carcinoma, Hepatocellular/complications ; Chronic Disease ; Female ; Graft Rejection/diagnosis ; Hepatitis/complications ; Humans ; Hyaluronic Acid/*blood ; Liver/pathology ; Liver Cirrhosis/complications/*diagnosis/pathology ; Liver Neoplasms/complications ; Liver Transplantation ; Male ; Middle Aged

BACKGROUND/AIMS: The aim of this study was to evaluate the feasibility of alpha-fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. METHODS: We retrospectively reviewed the medical records of HCC and cirrhosis patients at three hospitals. For each HCC patient, a cirrhosis patient matched for age, sex, etiology, and Child-Pugh classification was selected by simple random sampling. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. RESULTS: A total of 732 patients with HCC or cirrhosis were selected for each case and the control groups. The mean age was 54 years, and 72.4% of patients were male. The mean serum AFP levels in the HCC group and cirrhosis group were 3,315.6 and 117.2 ng/mL, respectively (p < 0.001). The area under the receiver operating characteristic curve for all HCC patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut-off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. CONCLUSIONS: The cut-off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, and that the appropriate value of AFP for the diagnosis of HCC may be 100 ng/mL rather than 200 ng/mL.
Aged ; Area Under Curve ; Carcinoma, Hepatocellular/*blood/*diagnosis/pathology ; Feasibility Studies ; Female ; Humans ; Liver Neoplasms/*blood/*diagnosis/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Predictive Value of Tests ; ROC Curve ; Republic of Korea ; Retrospective Studies ; alpha-Fetoproteins/*analysis

BACKGROUND/AIMS: Serum alpha-fetoprotein (AFP) is frequently used for the diagnosis of hepatocellular carcinoma (HCC). Most available data concerning AFP came from studies of patients with chronic hepatitis B or mixed etiologies. Studies concerning the diagnostic value of AFP for HCV-related liver cirrhosis (LC) are limited. We evaluated the factors influencing AFP elevation in the absence of HCC and analyzed the diagnostic value of serum AFP in HCC surveillance of HCV-related LC patients. METHODS: We enrolled 55 patients of HCV-related LC with HCC and 62 patients without HCC as a case-control study were analyzed. The sensitivity and specificity were calculated and the clinical and biochemical factors influencing serum AFP levels. RESULTS: The sensitivities and specificities of serum AFP for the detection of HCC in HCV-related LC were 72.7% and 59.7% for AFP> or =20 ng/mL, and 47.3% and 92.5% for AFP> or =100 ng/mL, respectively. Elevated serum AST was independently associated with elevated serum AFP level in HCV-related LC. In cases of AST< or =2 x upper limit of normal (ULN), the specificity of AFP> or =100 ng/mL for the diagnosis of HCC was 100%. However, in case of AST>2 x ULN, the specificity was 85.0% for AFP> or =100 ng/mL and 95.0% for AFP> or =200 ng/mL. CONCLUSIONS: Serum AST levels influence serum AFP level in HCV-related LC. In cases of AST< or =2 x ULN, AFP greater than 100 ng/mL highly indicates HCC in HCV-related LC, but not in case of AST>2 x ULN.
Aged ; Carcinoma, Hepatocellular/complications/*diagnosis/pathology ; Diagnosis, Differential ; Female ; Hepatitis C/*complications/immunology/virology ; Humans ; Liver Cirrhosis/*virology ; Liver Neoplasms/complications/*diagnosis/pathology ; Male ; Middle Aged ; Retrospective Studies ; Sensitivity and Specificity ; Tumor Markers, Biological/*blood ; alpha-Fetoproteins/*analysis

Despite septic arthritis is increasingly being reported in elderly patients with diabetes or alcoholism, reported cases of spontaneous bacterial arthritis in cirrhotic patients are extremely rare. We present the first reported case of K. pneumoniae septic arthritis and spontaneous bacterial peritonitis in a cirrhotic patient with hepatocellular carcinoma. K. pneumoniae, one of the most common causative organisms of spontaneous bacterial peritonitis in cirrhotic patients, was isolated from both the blood and the joint fluid, which suggests that the route of infection was hematogenous. After the treatment with cefotaxime and closed tube drainage, the condition of the patient was improved, and subsequently, the joint fluid became sterile and the blood cultures were proved negative. Therefore, this case provides further evidence for the mode of infection being bacteremia in cirrhotic patients and suggests that the enteric bacteremia in cirrhotics may cause infection in different organ systems.
Aged ; Animals ; Arthritis, Infectious/blood/*diagnosis/*microbiology ; *Carcinoma, Hepatocellular/pathology ; Fatal Outcome ; Female ; Humans ; Joints/chemistry/microbiology ; Klebsiella pneumoniae/*metabolism ; Liver Cirrhosis/*microbiology ; *Liver Neoplasms/pathology ; *Peritonitis/blood/microbiology/physiopathology