Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluated the significance of circulating bone marrow-derived endothelial progenitor cells (EPCs) in patients with hepatocellular carcinoma (HCC), a solid tumor with rich neovasculature. Eighty patients with HCC were recruited for the study, and 16 patients with liver cirrhosis and 14 healthy subjects were also included for comparison. Blood samples were taken before treatment. Total mononuclear cells were isolated from peripheral blood, preplated to eliminate mature circulating endothelial cells, and colony-forming units (CFUs) formed by circulating EPCs were counted. To validate the CFU scores, FACS quantification of EPCs using CD133, VEGFR2, and CD34 as markers was performed in 30 cases. Our study showed significantly higher mean CFU scores in patients with HCC compared to patients with cirrhosis and healthy controls (P = .001 and .009, respectively). Furthermore, the CFU scores of patients with HCC positively correlated with levels of serum alpha-fetoprotein (r = .303, P = .017), plasma VEGF (r = .242, P = .035), and plasma interleukin-8 (IL-8) (r = .258, P = .025). Patients with unresectable HCC had higher CFU scores than patients with resectable tumors (P = .027). Furthermore, for those who underwent curative surgery, higher preoperative CFU scores were observed in patients with recurrence within 1 year compared with those who were disease-free after 1 year (P = .013). In conclusion, higher circulating levels of EPCs are seen in patients with advanced unresectable HCC as compared to patients with resectable HCC or those with liver cirrhosis. Our evidence supports the potential use of circulating level of EPCs as a prognostic marker in patients with HCC.
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PMID:Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. 1700 19

The aim of the present study was to detect the correlation between the expression of vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2), ephrinB2 and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and carcinogenesis or portal vein tumor thrombus (PVTT) formation in human hepatocellular carcinoma (HCC). The expression of VEGF, Ang2, ephrinB2 and EG-VEGF was detected by RT-PCR in 54 cases HCC without PVTT (group A), 9 cases HCC with PVTT (group B), 10 normal liver tissues (group D) and 10 cirrhosis tissues (group C). The samples were also stained with CD34 by immunohistochemistry. Quantitation of microvessel density (MVD) and semi-quantitation of VEGF, Ang2, ephrinB2 and EG-VEGF expression were analyzed to find the relations. The MVD was 146.69 +/- 77.79, 214.07 +/- 54.41, 32.85 +/- 8.49 and 34.83 +/- 8.29 in group A-D respectively with significant difference (F = 19.77, P = 0.000). The MVD in group A was higher than that in group C P = 0.006, but lower than that in group B P < or = 0.05 or 0.01. The expression levels of VEGF165, VEGF189, Ang2 and EG-VEGF mRNA were significantly different among the groups. The expression levels of VEGF165, Ang2 and EG-VEGF mRNA in group A were all higher than those in group C, but lower than those in group B P < 0.05 or 0.01. The MVD was significantly correlated with VEGF165, VEGF189, Ang2 and EG-VEGF mRNA with Spearman's related coefficient being 0.764, 0.510, 0.640 and 0.366 in HCC (P = 0.000, 0.000 0.000 and 0.003). In conclusion VEGF, Ang2 and EG-VEGF mRNA may play a role in angiogenesis and carcinogenesis of HCC. They can promote PVTT formation in HCC by modulating angiogenesis.
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PMID:Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma. 1716 81

Angiogenesis progresses together with fibrogenesis during chronic liver injury. Hypoxia-inducible factor-1alpha (HIF-1alpha), a master regulator of homeostasis, plays a pivotal role in hypoxia-induced angiogenesis through its regulation of vascular endothelial growth factor (VEGF). The association between hypoxia, angiogenesis and VEGF expression has been demonstrated in experimental cirrhosis. However, expression of HIF-1alpha has yet to be reported. The aim of this study was to investigate the significance of HIF-1alpha expression during experimental liver fibrosis and the relationships between HIF-1alpha expression, VEGF expression and angiogenesis. Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN) (100 mg/kg, once a week). The serial sections from liver tissues were stained with anti-HIF-1alpha, anti-VEGF and anti-CD34 antibodies before being measured by light microscopy. Our results showed that HIF-1alpha expression gradually increases according to the severity of fibrosis (p<0.01). Moreover, its expression was found to be correlated with angiogenesis (r=0.916) and VEGF expression (r=0.969). The present study demonstrates that HIF-1alpha might have a role in the development of angiogenesis via regulation of VEGF during experimental liver fibrogenesis and suggests that this factor could be a potential target in the manipulation of angiogenesis in chronic inflammatory diseases of the liver.
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PMID:Hypoxia-inducible factor-1alpha expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis. 1761 45

P-glycoprotein (P-gp), which is encoded by the multidrug resistance gene (MDR-1); alpha fetoprotein (AFP); and vascular endothelium-associated antigens are well-known markers for human and canine hepatic diseases. We obtained liver tissues from 5 dogs with hepatocellular carcinoma (HCC) and 12 dogs with cirrhosis, and we performed histopathologic and immunohistochemical evaluations using anti-P-gp, anti-AFP, anti-CD31, and anti-CD34 antibodies. P-gp was expressed at higher levels in HCC than in cirrhotic livers ( P < .01), and was most commonly localized in biliary canaliculi and small ductuli. AFP was localized mainly in the cytoplasm in HCC ( P < .01) and in a few cases of cirrhosis. In both HCC and cirrhosis, the AFP-positive cells were morphologically similar to normal hepatocytes and showed an even cytoplasmic distribution of AFP. The endothelial markers CD31 and CD34 were used to investigate vascular distribution. CD31 was expressed strongly in the portal area and parenchyma in HCC, but it was rarely observed in the parenchyma in cirrhosis. CD34 expression could not be detected in both HCC and cirrhosis. This study constitutes the first comprehensive study of P-gp, AFP, and endothelial markers in canine HCC and cirrhosis. The importance of these markers in HCC and cirrhosis in dogs was demonstrated and provides a more accurate basis for a definitive diagnosis of HCC and cirrhosis in dogs.
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PMID:Cellular characterization of multidrug resistance P-glycoprotein, alpha fetoprotein, and neovascular endothelium-associated antigens in canine hepatocellular carcinoma and cirrhotic liver. 1784 32

The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, which include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN), and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" category requiring accurate distinction from well-differentiated and early hepatocellular carcinoma (HCC). Nodules in cirrhosis are usually detected by non-invasive imaging techniques, which are unable to discriminate malignant from non-malignant forms, particularly in the 1-2-cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with ultrasound (US)-detectable nodules. Histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (e.g. cell atypia, cell crowding, trabecular thickness, microacini) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34), or tumor markers (including HSP70 and glipican-3). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. Thus, the best diagnostic approach requires the integration ofclinical, morphological, and immunocytochemical information with imaging data (i.e. US pattern, perfusional pattern, helical computed tomography/magnetic resonance pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the category of "borderline" nodules that are mostly labelled as early, well differentiated HCC by Eastern pathologists and as HGDN by Western pathologsts. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between Eastern and Western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for proper clinical management and optimal therapy.
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PMID:Hepatocellular dysplastic nodules. 1787 73

A 47-year-old man underwent liver transplantation for cirrhosis secondary to hepatitis C and alcoholism. This was complicated by primary donor liver dysfunction and acute renal failure requiring dialysis. Gadolinium magnetic resonance cholangiopancreatography was performed 2 weeks post transplant, and a second successful liver transplant was performed 1 week later. Shortly after this, the patient developed rapidly progressive erythematous plaques over his abdomen, lower and upper limbs. There was marked oedema and skin induration. Fibrosis severely limited his mobility, leaving him wheelchair-bound. An abdominal plaque biopsy revealed increased dermal mucin and cellularity, with proliferation of spindled fibroblastic cells. Paraprotein was not detected in the serum. Facial sparing, the absence of serum paraprotein and the histopathological findings confirmed the diagnosis of nephrogenic systemic fibrosis. Immunohistochemical stains revealed CD34-positive spindle-shaped cells, and electron microscopy did not detect free gadolinium. Following improvement in renal function and various treatments, his plaques softened, fibrosis slowed and mobility partially improved. Gadolinium magnetic resonance cholangiopancreatography was performed following this improvement. Six weeks later, further progression of nephrogenic systemic fibrosis occurred despite normal renal function.
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PMID:Nephrogenic systemic fibrosis associated with liver transplantation, renal failure and gadolinium. 1818 50

Sinusoidal alterations unrelated to primary hepatocellular damage present without characteristic clinical findings and in these cases the liver biopsy is particularly important. Capillarization of sinusoids is characterized by closing of fenestration, formation of a basal membrane and by the expression of CD34 and is typical for active cirrhosis. In nodular regeneratory hyperplasia, capillarization indicates a local or general disturbance of perfusion. In large regenerative nodules, focal nodular hyperplasia and liver cell adenoma CD34-positive capillaries reflect afferent parts and CD34-negative sinusoids the efferent parts of the parenchymal vascular bed. HCC generally have a completely capillarized CD34-positive vascular bed. Hepatic angiosarcomas and epithelioid hemangioendotheliomas can be easily overseen in liver biopsies, if they spread along the sinusoids without detoriation of the acinar architecture and without significant alteration of the surrounding liver cell plates. Toxic damage of endothelial cells, post-sinusoidal stasis and sinusoidal hyperperfusion are the underlying pathogenetic principles of sinusoidal injury. Rupture and loss of the perisinusoidal reticulin fibres lead to peliosis hepatis. In these cases liver biopsy might disclose occlusion of the terminal liver veins (VOD). Perisinusoidal fibrosis can be caused by intrasinusoidal accumulation of pathologic cells, advanced intrasinusoidal macrophagocytic storage diseases and by activation of the vitamin A-storing hepatic stellate cells. Perisinusoidal amyloidosis can be the first sign of an underlying B-cell neoplasia.
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PMID:[Pathology along the liver sinusoids: endothelial and perisinusoidal findings]. 1821 Jan 8

Human interferon (IFN)-alpha is the standard therapy for chronic hepatitis C to prevent its progression to liver cirrhosis and hepatocellular carcinoma. Thrombocytopenia is one of the major adverse effects of IFN-alpha and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN-alpha inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-alpha did not inhibit colony formation of megakaryocytes from human CD34(+) hematopoietic stem cells. IFN-alpha did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN-alpha suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45(NF-E2), MafG. IFN-alpha also significantly reduced the number of human platelets but not megakaryocytes, and did not inhibit endomitosis of human megakaryocytes in immunodeficient NOD/Shi-scid/IL-2R gamma(null) (NOG) mice transplanted with human CD34(+) cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-alpha-induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN-alpha inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-alpha. These results defined the pathogenesis of IFN-alpha-induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.
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PMID:Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. 1852 49

The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, that include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" cathegory requiring an accurate distinction from well-differentiated and early hepatocellular carcinoma. Nodules in cirrhosis are usually detected by non-invasive imaging techniques, being the latter unable to discriminate malignant from non-malignant forms, particularly in the 1-2 cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with US detectable nodules. The histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (cell atypia, cell crowding, trabecular thickness, microacini etc) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34) or tumor markers (HSP70 and Glipican 3 among others). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. The best diagnostic approach thus requires the integration of clinical, morphological and immunocytochemical information with imaging data (US pattern, perfusional pattern, helical CT/MR pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the cathegory of "borderline" nodules, that are mostly labelled as early, well differentiated HCC by eastern pathologists and as HGDN by western pathologists. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between eastern and western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for a proper clinical management and optimal therapy.
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PMID:Hepatocellular dysplastic nodules. 1872 69

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is the fifth most common malignancy worldwide. HCC typically develops in the cirrhotic liver. Our preliminary results indicated that agrin, a heparan sulfate proteoglycan (HSPG) detected by us for the first time in the liver, accumulates in the basement membranes (BMs) of the cirrhotic liver and HCC. This novel finding prompted us to investigate the role of agrin in the pathogenesis and differential diagnosis of HCC. First, the previously unspecified monoclonal antibody anti-HSPG clone 7E12 was verified as anti-agrin, using mass spectrometry. Our subsequent experiments were carried out on specimens from 131 patients with chronic liver disease and 18 individuals with healthy liver, from 4 rats subjected to cirrhosis/HCC induction and 1 untreated control rat, as well as from cultured cells. In both human and rats, significantly increased expression of agrin in cirrhosis and HCC was demonstrated by immunohistochemistry (IHC), Western blot, and quantitative RT-PCR. By double immunofluorescent studies, agrin was localized to the muscular layer of blood vessel walls, the BM of bile ducts and ductular reaction, the microvessel walls of HCC, and occasionally the BM of hepatocellular tumor cells. Colocalization, gene expression, and mRNA in situ hybridization experiments suggested that the sources of agrin include vascular smooth muscle cells, epithelial cells of bile ducts and ductules, activated mesenchymal cells in the stroma of hepatocellular tumors, and occasionally tumor hepatocytes. Agrin in the BMs of bile ducts and blood vessels is thought to play an important role in the survival of bile duct epithelium and vascular endothelium, respectively. Thus, agrin may contribute to the formation of ductular reaction and HCC neovessels. As opposed to HCC neovessels that were consistently found agrin-positive, normal and cirrhotic sinusoids were always devoid of agrin, raising the possibility that agrin IHC might be useful in the differential diagnosis of benign versus malignant hepatocellular lesions. Agrin IHC was performed on 68 benign lesions (8 large regenerative nodules, 23 low-grade and 7 high-grade dysplastic nodules, 30 liver adenomas) and 29 malignant lesions (8 small HCC, 21 HCC), and was evaluated semi-quantitatively. Based on the results of IHC for agrin as well as CD34, a decision algorithm was devised that differentiated benign and malignant parenchymal lesions with a sensitivity of 93.1% and a specificity of 92.6%. Hence, we propose that agrin IHC might help distinguish between malignant hepatocellular lesions and their benign mimickers.
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PMID:[Selective deposition of agrin in the microvasculature of hepatocellular carcinoma: aspects in pathogenesis and differential diagnosis]. 1906 66


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