heparitin-sulfate and Liver-Cirrhosis

Proteoglycans are macromolecules formed by a protein core to which sugar chains are covalently attached. They are present on the cell surface and in the ECM of living things. In normal liver syndecan-1 is the dominant transmembrane proteoglycan, trace amounts of ECM proteoglycans are in the stromal components. The amounts of proteoglycans we studied increase in liver cirrhosis. In liver cancer abnormal localization of syndecan-1 and stroma rich in agrin was characteristic. The core proteins as well as the sugar chains of proteoglycans interact with and modulate the effect of regulatory factors. This implies that structural alterations of proteoglycans contribute to the development of malignant phenotype. Heparan sulfate chains of liver cancer are undersulfated with decreased or altered biological activity. Their binding capacity for transcription factor decreases, and they do not inhibit topoisomerase I enzyme. Truncated form of syndecan-1 lacking the extracellular domain of the molecule induces differentiation of hepatoma cell line and inhibits the shedding of syndecan-1. This phenomenon calls attention to the importance of syndecan-1 shedding in the regulation of cell behavior.

Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Heparitin Sulfate; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Membrane Glycoproteins; Proteoglycans; Signal Transduction; Syndecan-1; Syndecans

Topics: Animals; Basement Membrane; Collagen; Gene Expression Regulation; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Laminin; Liver; Liver Cirrhosis; Promoter Regions, Genetic; Proteoglycans

Decreased antithrombin III (ATIII) activity and large splenic vein diameter (SVD) are risk factors for portal vein thrombosis (PVT) after splenectomy in liver cirrhosis with portal hypertension. Antithrombin III concentrates can prevent PVT. This study was designed to stratify risks for PVT after splenectomy in cirrhotic patients and to develop prophylactic protocols for PVT.. In 53 patients (testing cohort), the cutoff level of preoperative ATIII activity (≤60%) was evaluated for administration of ATIII concentrates. Antithrombin III activity and SVD were re-evaluated as criteria for prophylaxis of PVT. In 57 patients (validation cohort), the risk stratification of PVT and prophylactic protocols were validated.. In the testing cohort, 10 (19%) of 53 patients had PVT. Risk level of PVT was stratified and prophylactic protocols were developed. Patients at low risk (ATIII activity ≥70% and SVD <10 mm) were not treated; those at high risk (ATIII activity <70% or SVD ≥10 mm) received ATIII concentrates (1,500 U/day) for 3 days; and those at highest risk (SVD ≥15 mm) received ATIII concentrates for 3 days, followed by danaparoid sodium (2,500 U/day) for 14 days and warfarin. In the validation cohort, 0 of 14 low-risk and 2 of 32 high-risk patients had PVT. Although 8 of 11 patients at highest risk had temporary PVT, it disappeared within 3 months postoperatively. Finally, only 2 (3.5%) of 57 patients had PVT.. Risk stratification of PVT after splenectomy and prophylaxis with ATIII concentrates and danaparoid sodium dramatically reduced the incidence of PVT.

Topics: Adult; Aged; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Clinical Protocols; Decision Support Techniques; Dermatan Sulfate; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparitin Sulfate; Humans; Hypertension, Portal; Laparoscopy; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Postoperative Complications; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Splenectomy; Venous Thrombosis; Warfarin

Chronic liver diseases have both high incidence and mortality rates; therefore, a deeper understanding of the underlying molecular mechanisms is essential. We have determined the content and sulfation pattern of chondroitin sulfate (CS) and heparan sulfate (HS) in human hepatocellular carcinoma and cirrhotic liver tissues, considering the etiology of the diseases. A variety of pathological conditions such as alcoholic liver disease, hepatitis B and C virus infections, and primary sclerosing cholangitis were studied. Major differences were observed in the total abundance and sulfation pattern of CS and HS chains. For example, the 6-O-sulfation of CS is fundamentally different regarding etiologies of cirrhosis, and a 2-threefold increase in HS N-sulfation/O-sulfation ratio was observed in hepatocellular carcinoma compared to cirrhotic tissues.

Topics: Carcinoma, Hepatocellular; Chondroitin Sulfates; Glycosaminoglycans; Heparitin Sulfate; Humans; Liver Cirrhosis; Liver Neoplasms; Pilot Projects

Portal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis.. This retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1-5 and days 8-12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT.. All patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis.. Danaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Humans; Liver Cirrhosis; Male; Portal Vein; Prognosis; Retrospective Studies; Venous Thrombosis

Portal vein thrombosis (PVT) is a serious complication in liver cirrhosis with portal hypertension. We examined the treatment, recurrence and prognosis of PVT in cirrhotic patients.. The study subjects were all 90 cirrhotic patients with PVT treated with danaparoid sodium (DS) at our department between July 2007 and September 2016. The mean age was 68 years and mean Child-Pugh score was 7. All patients received 2500 U/day of DS for 2 weeks, and repeated in those who developed PVT recurrence after the initial therapy.. Complete response was noted in 49% (n = 44), partial response (shrinkage ≥70%) in 33% (n = 30), and no change (shrinkage <70%) in 18% (n = 16) of the patients after the initial course of treatment. DS treatment neither caused adverse events, particularly bleeding or thrombocytopenia, nor induced significant changes in serum albumin, total bilirubin, prothrombin time, and residual liver function. Re-treatment was required in 44 patients who showed PVT recurrence and 61% of these responded to the treatment. The cumulative recurrence rates at 1 and 2 posttreatment years were 26 and 30%, respectively. The recurrence rates were significantly lower in patients with acute type, compared to the chronic type (p = 0.0141). The cumulative survival rates at 1 and 3 years after treatment (including maintenance therapy with warfarin) were 83 and 60%, respectively, and were significantly higher in patients with acute type than chronic type (p = 0.0053).. We can expect prognostic improvement of liver cirrhosis by warfarin following two-week DS therapy for the treatment of PVT in patients with liver cirrhosis safety and effectiveness. An early diagnosis of PVT along with the evaluation of the volume of PVT on CT and an early intervention would contribute to the higher efficacy of the treatment.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Chondroitin Sulfates; Contrast Media; Dermatan Sulfate; Female; Heparitin Sulfate; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Recurrence; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome; Venous Thrombosis; Warfarin

An 84-year-old woman with hepatitis C virus-related cirrhosis, hepatocellular carcinoma and atrial fibrillation, who presented with hematemesis, was initially treated with endoscopic variceal ligation (EVL) for an esophageal varix hemorrhage. However, computed tomography (CT) upon admission had revealed portal vein thrombosis, despite having received warfarin for existing atrial fibrillation. We subsequently initiated a 2-week treatment with danaparoid;warfarin being discontinued in order to reduce the risk of re-hemorrhage. A follow-up CT after treatment revealed complete reduction of the portal vein thrombosis. This is the first successful report of danaparoid use in the treatment of portal vein thrombosis that developed in a patient who had received warfarin.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Portal Vein; Thrombosis; Warfarin

Heparan sulfate (HS), due to its ability to interact with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HS-modifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3-O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6-O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3-O-sulfated and partially 6-O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC.

Topics: Agrin; Animals; Carcinoma, Hepatocellular; Chronic Disease; Disaccharides; Focal Nodular Hyperplasia; Glucuronidase; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfotransferases; Syndecan-1

We report a case of hepatitis B type liver cirrhosis with portal venous thrombosis in which danaparoid sodium was very effective. The portal venous thrombosis in this case disappeared 2 weeks commencing after administration of danaparoid sodium. The patient had not adverse effects or complications such as hemorrhage, and the clinical course was good. We consider that danaparoid sodium is an anticoagulant unlikely to cause adverse effects such as hemorrhage, and that it might be effective for treatment of portal venous thrombosis. We intend to examine the indications of treatment with danaparoid sodium, clarify the best administration method, and establishment of maintenance therapy by investigating more cases.

Topics: Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Heparitin Sulfate; Hepatitis B; Humans; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Tomography, X-Ray Computed; Ultrasonography; Venous Thrombosis

Bacterial infections have been postulated as a trigger for variceal bleeding in cirrhotic patients, and impair coagulation evaluated by thrombelastography (TEG). Endogenous heparinoids have been detected after variceal bleeding and during liver transplantation in some cirrhotics using heparinase-modified-TEG.. To assess if bacterial infection is associated with endogenous heparinoids in cirrhotics, thus impairing coagulation.. Native and heparinase-modified-TEG (cleavage of heparin and heparan-sulphate) was performed in 60 cirrhotics (Grade A, 2; B, 30; C, 28): 30 infected [septicaemia, 6 (culture positive); 6 (culture negative); spontaneous bacterial peritonitis, 10; chest infection, 4; others, 4], 30 not infected, and five infected patients without liver diseases, comparing TEG parameters r, alpha, and ma. Eight cirrhotics were studied before and after infection. The diagnosis of presence and type of infection was based on international standard criteria.. A significant heparin effect was found only in infected cirrhotics (28 of 30) with significant changes in r (P=0.0003), alpha (P<0.0001), and ma (P<0.0001), but in none of those not infected. This effect completely reversed in the eight evaluated after resolution of infection. There was no heparin effect in infected non-cirrhotics.. A heparin effect was only found in cirrhotic patients with infection, further confirming that infection significantly modifies coagulation in cirrhotic patients.

Topics: Adult; Bacterial Infections; Blood Coagulation; Female; Gastrointestinal Hemorrhage; Heparin; Heparin Lyase; Heparinoids; Heparitin Sulfate; Hepatitis, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Peritonitis; Thrombelastography

Immunolocalization of a fibronectin-binding proteoglycan (PG-P1) in relation to fibronectin, type IV collagen and laminin, in normal and fibrotic human liver was investigated by light and electron microscopy. HS-42, which is a monoclonal antibody to PG-P1 and is reported to recognize a heparan sulfate proteoglycan named HSPG2/perlecan, was used for this purpose. Light microscopy in the human liver with minimal changes revealed that PG-P1 was present along the hepatic sinusoids as well as fibronectin and type IV collagen, whereas laminin was only weakly detected. In portal areas, PG-P1 was only localized on basement membranes around bile duct systems and blood vessels, as well as laminin and type IV collagen, while fibronectin was scarcely detected in basement membranes. In the fibrotic liver, fibronectin was abundant in necrotic and/or newly fibrosing areas, while PG-P1 was absent in these regions. Using immunoelectron microscopy, PG-P1 was localized in the space of Disse in nearly normal livers and was only detected on basement membranes in portal tracts. In fibrotic livers, PG-P1 in the space of Disse occasionally showed a basement-membrane-like deposition in parallel with the increased light microscopical deposition of laminin in this area, suggesting the positive participation of PG-P1 in the sinusoidal capillarization. Most capillary and sinusoidal endothelial cells, and rarely bile epithelial cells revealed the reaction products of PG-P1 in their rough endoplasmic reticulum and small vesicles. Thus, it was suggested that these cell types are mainly, if not wholly, responsible for PG-P1 production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Biopsy; Collagen; Female; Fibronectins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunoenzyme Techniques; Laminin; Liver; Liver Cirrhosis; Male; Microscopy, Immunoelectron; Middle Aged; Proteoglycans

The behaviour of extracellular matrix glycoproteins (fibronectin, laminin, basement membrane heparan-sulphate proteoglycan, type III, IV and V collagens) has been investigated in a sequential model of experimental hepatic fibrosis, using an immunofluorescence technique. The presence of some basement membrane macromolecules (such as type IV and V collagens, laminin and basement membrane heparan-sulphate proteoglycan) is detectable only in the early stages of septa formation, while type III collagen and fibronectin persist in late septa. These data suggest that hepatic fibroplasia proceeds through different steps in which stromal glycoproteins are preferentially engaged, as happens during organogenesis.

Topics: Animals; Basement Membrane; Chondroitin Sulfate Proteoglycans; Collagen; Disease Models, Animal; Extracellular Matrix; Fibronectins; Fluorescent Antibody Technique; Glycoproteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Laminin; Liver Cirrhosis; Male; Rats; Rats, Inbred Strains; Swine

Acidic glycosaminoglycan (AGAG) components in normal human liver and at different stages of liver cirrhosis were studied at the constitutional disaccharide level by enzymatic assay methods. The AGAG content in human cirrhotic liver was 5-6 times that in the normal state. The most predominant AGAG components in normal human liver tissue were heparan sulfates (HS) which accounting for 63% of the total AGAG, followed by a moderate amount of dermatan sulfate (DS) and small amounts of chondroitin sulfate isomers and hyaluronic acid (HA). In addition, the oversulfated DS detected in human liver. The increase in both HS and DS content reflects an increase in total AGAG with advancing liver cirrhosis. The ratio of non-sulfated AGAG, HA plus chondroitin, to DS plus its oversulfated isomer was 0.24 in the normal state but it increased to 0.80 at the early stage of liver cirrhosis. However, the ratio decreased to 0.36 and 0.21 at the typical and advanced stages of liver cirrhosis, respectively, with progress in the fibrotic process.

Topics: Chondroitin Sulfates; Chromatography, Paper; Dermatan Sulfate; Electrophoresis; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Liver; Liver Cirrhosis

The extractable and nonextractable collagen and glycosaminoglycuronans (GAG) were estimated and characterized in 32 dried, defatted human livers obtained at necropsy. 10 had normal livers. 22 of the 32 livers were from patients who drank in excess: 5 had fatty livers, 7 had alcholic hepatitis, and 10 had cirrhosis. Livers with alcoholic hepatitis or cirrhosis had significantly increased total and 1 N NaCl-extractable collagen. Only alcoholic hepatitis livers had significantly increased Tris-buffer-extractable GAG, but the amino acid composition of these GAG (proteoglycans) was no different from that of normal livers. The major fraction of these GAG had isoelectric pH (pI)

Topics: Alcoholism; Amino Acids; Chemical and Drug Induced Liver Injury; Chondroitin; Chromatography, Gel; Collagen; Connective Tissue; Dialysis; Fatty Liver; Glucosamine; Glycoproteins; Glycosaminoglycans; Heparitin Sulfate; Hexosamines; Humans; Hyaluronic Acid; Hydroxyproline; Isoelectric Focusing; Liver; Liver Cirrhosis