Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human hepatoma cell line, Hep G2, was analyzed for the ability to synthesize and secrete several coagulation proteins. Using specific radioimmunoassays, factor X, prothrombin, and antithrombin III were present in 8-day culture supernatants at 62, 405, and 1,220 ng/mL, respectively. Factor IX was not detected, either in supernatants or in cell extracts. Intrinsically labeled factor X was secreted as a single-chain polypeptide of 66,000 daltons, as measured by sodium dodecylsulfate-polyacrylamide gels under nonreduced and reduced conditions. Immunoblots of Hep G2 supernatants and normal human plasma also indicate the presence of single-chain factor X. These findings support the hypothesis of a postsecretion proteolytic cleavage of factor X into the two-chain form. Prothrombin and antithrombin represented their plasma protein counterparts structurally, with molecular weights of 73,000 and 61,000, respectively. Secreted factor X, prothrombin, and antithrombin III were biologically active, as determined in coagulation or chromogenic assays, and all three activities were neutralized by monospecific antibodies. Vitamin K increased the quantity of prothrombin secreted by twofold, without affecting the rate of secretion over a five-day culture period, and had an apparent transient inhibitory effect on secretion of antithrombin III. Warfarin caused a three to fourfold decrease in the rate and quantity of secreted prothrombin, but did not affect intracellular concentrations. The intracellular and extracellular concentrations and rate of secretion of antithrombin III were not modulated by warfarin. These data suggest that the Hep G2 cell line may provide a useful model for assessing the regulation of biosynthesis and secretion of human coagulation proteins.
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PMID:Human hepatoma cells secrete single chain factor X, prothrombin, and antithrombin III. 632 78

The mechanisms by which blood levels of prothrombin (PT) are regulated in the vitamin K-sufficient state are unknown. We have studied PT synthesis by Reuber H-35 rat hepatoma cells exposed to vitamin K and [3H]leucine in serum-free cultures. Administration to the culture system of exogenous bovine PT and rat PT was characterized by increases in endogenous PT synthesis and secretion of 2- and 3-fold, respectively. This induction required endogenous proteolytic degradation of PT. Studies conducted with bovine PT fragment 1 (residues 1-156) demonstrated up to 5-fold increases in PT synthesis. This induction was dose dependent and saturable. Addition of bovine PT chymotryptic fragments to the cells indicated that the NH2-terminal peptide of prothrombin (residues 1-42) contained the requisite structural elements for the induction. Peptide-bound gamma-carboxyglutamate residues were required for the observed stimulation of PT synthesis. These results suggest that PT synthesis might be regulated physiologically by the products formed during its normal turnover and consumption during blood coagulation.
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PMID:Induction of prothrombin synthesis by prothrombin fragments. 694 25

Factor X in plasma is a gamma-carboxylated two-chain glycoprotein which, in activated form, plays a pivotal role in blood coagulation. We have utilized purified rat Factor X antibody, coupled to Sepharose, to isolate and characterize Factor X in rat liver, plasma, and hepatoma cells. Rat factor X is synthesized as a single chain precursor (Mr = 63,000). It is this form which undergoes vitamin K-dependent carboxylation in rat liver microsomes. Only after secretion is Factor X converted into its two-chain mature form. Single chain X synthesis and secretion in hepatoma cells is enhanced by vitamin K. The amount of single chain X secreted by these cells is one-half that of prothrombin. The NH2-terminal gamma-carboxylated fragments of prothrombin which induce prothrombin synthesis (Graves, C. B., Munns, T. W., Carlisle, T. L., Grant, G. A., and Strauss, A. W. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 4772-4776) also induce single chain X synthesis by hepatoma cells. We propose that synthesis of all vitamin K-dependent proteins may be regulated by this common control mechanism.
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PMID:Rat factor X is synthesized as a single chain precursor inducible by prothrombin fragments. 713 Jan 96

Five autopsy cases of peliosis hepatis occurring as a late complication of thorotrast (ThO2) liver disease are described. The liver contained many blood-filled cystic spaces of various sizes. Marked sinusoidal dilatation, disruption of cell cords and reticulin fiber framework, and cystic dilatation of sinusoids seem to represent the developmental stages of peliosis hepatis in sequence. Of the five cases, two had no other liver disease except for hepatic fibrosis, and the other three had associated neoplasms, such as angiosarcoma, hepatocellular carcinoma, cholangiocarcinoma, benign hemangioma, and their combinations. Peliosis hepatis seemed to have directly contributed to the patient's death in four cases. The most characteristic clinical feature was the fulminant terminal course with massive ascites, deep jaundice, and hepatic failure, often accompanied by hepatorenal syndrome and tendency to hemorrhage. Liver function study suggested progressive hepatic insufficiency with reduction in serum albumin, prothrombin and the clearance rate for test dyes, and increase in bilirubin. Clinical diagnosis was almost impossible without biopsy.
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PMID:Peliosis hepatis as a late and fatal complication of thorotrast liver disease. Report of five cases. 734 56

The clinical usefulness of plasma abnormal prothrombin, defined as protein induced by vitamin K absence or antagonist II: (PIVKA II) as a tumour marker for hepatocellular carcinoma (HCC) and other liver diseases has been evaluated. PIVKA II concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) with monoclonal antibody that reacts with PIVKA II but does not cross-react with normal prothrombin. Seventy four patients (74%) out of 100 with HCC had abnormal PIVKA II levels above 0.5 AU/ml (median = 3.4 AU/ml). The level was above 1.0 AU/ml in 66 (66%) of the patients. In contrast the level of PIVKA II was low in patients with bilharzial periportal fibrosis (median = 0.09 AU/ml), patients with liver cirrhosis (median = 0.13 AU/ml), patients with hepatitis (median = 0.025 AU/ml), and essentially undetectable in all the 34 controls. The diagnostic ability of serum alphafoetoprotein (AFP) was also evaluated in these patients. AFP alone can diagnose 51% of the HCC cases. Of the remaining patients with low or negative AFP levels (65%) can be diagnosed using PIVKA II. Abnormal prothrombin is a potential marker for the laboratory diagnosis of hepatocellular carcinoma.
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PMID:Acarboxy prothrombin (PIVKA II) as a tumour marker for hepatocellular carcinoma and other liver diseases. 749 46

We measured des-gamma-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 alpha-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.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical evaluation of plasma des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes. 750 17

The serum level of alpha-L-fucosidase activity has been suggested as a useful marker in the diagnosis of hepatocellular carcinoma, although the precise mechanism behind the elevation of this parameter has not been determined. We found that the serum alpha-L-fucosidase activity level was significantly higher in 67 patients with hepatocellular carcinoma (695.1 +/- 245.5 nmol/ml/hr) than in 47 patients with cirrhosis (389.1 +/- 188.2 nmol/ml/hr; p < 0.001) and in 54 controls (202.0 +/- 104.6 nmol/ml/hr; p < 0.001). However, alpha-L-fucosidase activity was not correlated with tumor size (r = 0.134), whereas the alpha-fetoprotein level was correlated with tumor size (r = 0.580, p < 0.001). When 515.8 nmol/ml/hr was taken as the cutoff value (mean value in the controls plus 3 standard deviations), alpha-L-fucosidase activity was above the cutoff value in 12 of the 17 patients with a hepatocellular carcinoma less than 2 cm in diameter, in 28 of the 37 patients with a hepatocellular carcinoma less than 3 cm in diameter and in 52 of the 67 patients with hepatocellular carcinoma. In contrast, only 10 of the 47 patients with cirrhosis had levels above the cutoff value. These findings suggest that an increase in serum alpha-L-fucosidase activity in patients with cirrhosis may be a marker for detecting a hepatocellular carcinoma, especially a small tumor, because alpha-fetoprotein and des-gamma-carboxy-prothrombin are less promising as tumor markers.
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PMID:Serum alpha-L-fucosidase activity and tumor size in hepatocellular carcinoma. 751 63

The blood coagulation and fibrinolysis of 33 patients with compensated liver cirrhosis and 31 patients with hepatocellular carcinoma were examined using several markers, namely thrombin-antithrombin III complex (TAT), plasmin-alpha 2 plasmin inhibitor complex (PIC), antithrombin-III (AT-III) and prothrombin time, and the relationship between these markers, endotoxemia, and TNF-alpha was examined. These patients had no complications due to hepatic failure, such as infections, encephalopathy, ascites, G-I bleeding and clinical DIC. PIC was not elevated, but TAT tended to be elevated in LC and significantly elevated in HCC. AT-III was decreased in LC and HCC, and the blood endotoxin was partly positive in LC and HCC, but was not correlated with AT-III or PT. The TAT level in the blood-endotoxin-positive patients measured by endospecy methods was higher than that in the negative patients, and was significantly correlated with the blood endotoxin level in the LC and HCC patients (r = 0.57, r = 0.88, p < 0.01). No relationship was observed between TNF-alpha and blood endotoxin. In conclusion, (1) blood coagulability was activated already in compensated LC and HCC, but was not connected with fibrinolysis, (2) the activation of coagulability was closely related with endotoxemia, and (3) TNF-alpha was not correlated with blood endotoxin or TAT.
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PMID:[Blood coagulation and fibrinolysis in relation to endotoxemia in liver cirrhosis and hepatocellular carcinoma]. 756 21

To investigate the pathogenesis of fibrinolysis in liver disease, antithrombin III (AT III) activity, prothrombin fragment (F1 + 2) and d-dimer (D-DI) were measured in 50 patients with liver disease and in 17 healthy controls. Moreover, 4 patients with cirrhosis were randomly assigned to receive either an intravenous infusion of AT III (at two different dosages) or placebo, with a crossover design. Increased levels of D-DI were detected in patients with cirrhosis and hepatocellular carcinoma in comparison both with control subjects and with patients with acute hepatitis or mild chronic liver disease. An inverse correlation was observed between AT III and D-DI (r = -0.755, P < 0.001, simple linear regression), while no correlation was found between D-DI or AT III and F1 + 2. The correlation of the deficiency of AT III activity by infusion of human AT III did not result in any significant change (P0.10, analysis of variance for repeated measures) of the plasma concentration of either D-DI or F1 + 2, in comparison to placebo. Thus, advanced forms of chronic liver disease, but not acute hepatitis and mild forms of chronic liver disease, are associated with increased plasma concentrations of markers of fibrinolysis, which are inversely correlated with AT III activity. However, the correction of the deficient AT III activity does not affect the plasma concentration of either D-DI or F1 + 2, thence not supporting the hypothesis that enhanced fibrinolysis in advanced liver disease is the result of low-grade disseminated intravascular coagulation.
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PMID:Deficient antithrombin III activity and enhanced fibrinolysis in patients with liver disease: evidence against a cause-effect relationship. 757 84

In this review, the current approach to the screening, diagnostic evaluation, staging, and treatment for hepatocellular carcinoma (HCC) is outlined. The serum alpha-fetoprotein (AFP) level and abdominal ultrasonography (US) remain the cornerstones of screening protocols for HCC. Other serum marker proteins, such as abnormal serum prothrombin (PIVKA-II), when used in conjunction with AFP, can increase the yield for HCC. For diagnosis and staging of HCC, other imaging modalities employed include CT scan, infusion hepatic angiography, CT with arterial portography or iodized oil enhancement, MRI with contrast enhancement, intraoperative US, and US-guided fine-needle aspiration cytology and biopsy. Treatment options which have afforded some improvement in survival and tumor regression include surgical resection, orthotopic liver transplantation, percutaneous injection of ethanol, arterial chemoembolization, cryotherapy, and systemic or regional chemotherapy. Despite these advances, the diagnosis of HCC still portends a dismal prognosis.
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PMID:Hepatocellular carcinoma: update on diagnosis and treatment. 758 35


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