Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (FGF) is thought to be involved in carcinogenesis and, to clarify its clinical significance, the study of its blood level in cancer patients is important. Plasma levels of basic FGF are reported to be elevated in some cancers. However, little is known of basic FGF levels in plasma in hepatocellular carcinoma (HCC). In this study, we measured basic FGF plasma levels in patients with chronic liver disease and compared the levels in chronic hepatitis (CH), liver cirrhosis (LC), and HCC. We also examined whether these levels were related to serum levels of asparate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, leucine aminopeptidase, total bilirubin, total protein, and albumin, and to the indocyanine green test (i.e., liver function tests) and to type III procollagen. 7S domain of IV type collagen, and hyaluronic acid (i.e., markers of liver fibrosis). Levels of basic FGF, determined by a quantitative "sandwich" enzyme immunoassay, were significantly elevated with the progression of liver disease; being 3.67 +/- 2.37 (mean +/- SD). 7.78 +/- 6.61, and 12.37 +/- 7.67 pg/ml in the CH, LC, and HCC groups, respectively. FGF levels were elevated to a greater extent in the HCC patients than in the CH (P < 0.0001) and LC patients (P = 0.0117). Levels were higher in LC than in CH (P = 0.0204). None of the liver function test findings or levels of markers of liver fibrosis were correlated with levels of basic FGF. These results suggest that circulating basic FGF could serve as a new indicator of the progression of chronic liver disease. The extremely elevated plasma of level basic FGF in the HCC group suggests that basic FGF may be related to the development of HCC.
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PMID:Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease. 905 7

Matrix metalloproteinases (MMPs) have the ability to degrade basement membranes and may thus play an important role in extracellular matrix turnover in liver fibrosis and carcinogenesis. Serum levels of MMPs have been suggested as diagnostic markers in these processes. We measured serum MMP-2 and MMP-9 by ELISA in 91 patients with chronic liver disease, including 25 patients with hepatocellular carcinoma (HCC), and in 60 controls. MMP-2 was significantly higher in patients with chronic liver disease compared to controls, and increased with Child-Pugh class. There was a significant correlation between MMP-2 and liver function (bilirubin, albumin, and prothrombin time), and a strong opposite correlation between MMP-9 and these parameters. MMP-2 levels in patients with HCC were significantly higher than in controls, but comparable to patients with chronic liver disease without this malignancy. MMP-9 yielded no significant differences between patients with or without HCC and controls. Serum MMP-2 and to a lesser extent MMP-9 correlate with the severity of liver disease and may reflect changes in extracellular matrix remodeling. Due to a considerable overlap in patients with chronic liver disease with or without HCC, MMP-2 and MMP-9 can not be used as a diagnostic marker for HCC.
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PMID:Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma. 1266 27

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced by Fusarium verticillioides. Dietary exposure to FB1 has been linked to human cancer in certain parts of the world, and treatment with FB1 causes oval cell proliferation and liver tumors in rats. To study the potential role of oval (liver progenitor) cells in the cellular pathogenesis of FB1-induced liver tumors, we gave male F344 rats prolonged treatment with FB1 for 25 weeks, followed by return to control diet until 50 weeks ('stop study'). The time course of FB1-induced liver lesions was followed by examination of serial liver biopsies at set time intervals and post-mortem liver tissue at the end of the study. The effects of different FB1 treatment regimens (5 versus 25 weeks), as well as the modulating effect of 2-acetylaminofluorene (2-AAF), on the kinetics of oval cell proliferation and development of liver tumors were compared. Prolonged treatment with FB1 in normal diet caused persistent oval cell proliferation and generation of both hepatic adenomas and cholangiofibromas (CFs). These liver lesions occurred in the setting of chronic toxic hepatitis and liver fibrosis/cirrhosis, similar to that seen in human hepatocarcinogenesis. Some adenomas and CFs were dysplastic, and one post-mortem liver contained a hepatocellular carcinoma. OV-6+ oval cells were noted in close relation to proliferative neoplastic liver lesions, and some of these lesions expressed OV-6, suggesting that all these cell types were derived from a common progenitor cell. 2-AAF enhanced the size of FB1-induced glutathione S-transferase pi+ hepatocellular lesions and the incidence of CFs in post-mortem liver specimens, but this was not statistically significant. In conclusion, this study supports the involvement of dietary FB1 in liver carcinogenesis in male F344 rats. Oval cells may be the source of both the hepatocellular and cholangiocellular tumors induced by prolonged treatment with FB1. 2-AAF appears to have an enhancing effect on FB1-induced liver tumors, presumably due to its potent inhibitory effects on hepatocyte regeneration.
Carcinogenesis 2004 Jul
PMID:Fumonisin B1-induced hepatocellular and cholangiocellular tumors in male Fischer 344 rats: potentiating effects of 2-acetylaminofluorene on oval cell proliferation and neoplastic development in a discontinued feeding study. 1498 22

Multifaceted evidence links the development of liver tumours to the activation and proliferation of adult liver progenitor (oval) cells during the early stages of chronic liver injury. The aim of this study was to examine the role of the peroxisome proliferator activated receptors (PPARs): PPARalpha, delta and gamma, in mediating the behaviour of liver progenitor cells during pre-neoplastic disease and to investigate their potential as therapeutic targets for the treatment of chronic liver injury. We observed increased liver expression of PPARalpha and gamma in concert with expanding oval cell numbers during the first 21 days following commencement of the choline deficient, ethionine supplemented (CDE) dietary model of carcinogenic liver injury in mice. Both primary and immortalized liver progenitor cells were found to express PPARalpha, delta and gamma, but not gamma2, the alternate splice form of PPARgamma. WY14643 (PPARalpha agonist), GW501516 (PPARdelta agonist) and ciglitazone (PPARgamma agonist) were tested for their ability to modulate the behaviour of p53-immortalized liver (PIL) progenitor cell lines in vitro. Both PPARdelta and gamma agonists induced dose-dependent growth inhibition and apoptosis of PIL cells. In contrast, the PPARalpha agonist had no effect on PIL cell growth. None of the drugs affected the maturation of PIL cells along either the hepatocytic or biliary lineages, as judged by their patterns of hepatic gene expression prior to and following treatment. Administration of the PPARgamma agonist ciglitazone to mice fed with the CDE diet for 14 days resulted in a significantly diminished oval cell response and decreased fibrosis compared with those receiving placebo. In contrast, GW501516 did not affect oval cell numbers or liver fibrosis, but inhibited CDE-induced hepatic steatosis. In summary, PPARgamma agonists reduce oval cell proliferation and fibrosis during chronic liver injury and may be useful in the prevention of hepatocellular carcinoma.
Carcinogenesis 2005 Oct
PMID:Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta. 1591 8

We previously reported that a sub-necrogenic dose (20 mg/kg) of diethylnitrosamine (DENA) can induce the development of liver cancer when rats undergo a fasting-re-feeding regimen. The present study was undertaken to establish whether fasting followed by re-feeding builds up mechanisms able to trigger liver fibrosis, eventually leading to cirrhosis and cancer. Adult male rats, for fasted 4 days, were given 20 mg/kg of DENA after 1 day of re-feeding; in parallel, consistently fed animals receiving 20 mg/kg (sub-necrogenic) or 200 mg/kg (necrogenic dose) of DENA were used as negative and positive controls, respectively. All three groups were then subjected to the 2-acetylaminofluorene/carbon tetrachloride promoting regimen. Fasting induced moderate apoptosis in liver tissue, as evidenced by increased levels of transforming growth factor-beta1 (TGF-beta1) and Bax proteins and by a dramatic drop in the level of Bcl-2. Subsequent re-feeding caused all changes to revert except TGF-beta1 up-regulation. Histological findings of inflammation and fibrosis were consistently associated with increased production of TGF-beta1, the inflammatory cytokine with the most pronounced profibrogenic action. Thus, up-regulation of TGF-beta1 expression appears as a major mechanism by which the fasting-re-feeding regimen predisposes to initiation and promotion of liver carcinogenesis in rats. Avoiding fasting-re-feeding could be considered in the nutritional status of patients with liver fibrosis.
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PMID:Early induction of TGF-beta1 through a fasting-re-feeding regimen promotes liver carcinogenesis by a sub-initiating dose of diethylnitrosamine. 1654 46

Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH.
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PMID:Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. 1700 38

Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma (HCC). Hemosiderosis has also been described to trigger carcinogenesis. A significant iron overload, as found in hereditary hemochromatosis (HHC), is a risk factor for HCC and may also promote the symptoms of porphyria cutanea tarda (PCT). A 68-year old male patient presented to our clinic with a suspected HCC, elevated alpha-fetoprotein but normal liver function tests. He reported a 25 year-old history of vitiligo upon exposure to sunlight. The patient underwent an extended left hemihepatectomy, and the recovery was uneventful, with the exception of a persistent hyperbilirubinemia. Perfusion problems and extrahepatic cholestasis were ruled out by CT-scan with angiography and MR-cholangiopancreatography. However, MRI showed an iron overload. Histology confirmed the HCC (pT3, pN0, G3, R0) and revealed a portal fibrosis and hemosiderosis. Based on the skin lesions we suspected a PCT that was confirmed by laboratory tests showing elevated porphyrin, uroporphyrin, coproporphyrin and porphobilinogen. Concurrently, molecular diagnostics revealed homozygosity for the C282Y mutation within the hemochromatosis HFE gene. After phlebotomy and normalization of liver function tests the patient was discharged. This is the first case ever showing the unusual combination of HCC in a fibrotic liver with HHC and PCT. This diagnosis not only warrants oncological follow-up but also symptomatic therapy to normalize iron metabolism and thereby improve liver function and alleviate the symptoms of HHC and PCT. Thus progression of fibrosis may be prevented and liver regeneration supported.
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PMID:An unhappy triad: hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-a case report. 1746 5

Hepatic fibrosis is a wound-healing process in the liver with acute and chronic injury and is characterized by an excess production and deposition of extracellular matrix components. Hepatic stellate cells as well as portal fibroblasts play a pivotal role in the liver fibrogenesis. Regarding the origin of these mesenchymal cells, two hypotheses emerge. One hypothesis argues in favor of BM-derived progenitor cells and a second hypothesis favors epithelial-mesenchymal transition (EMT) in the local formation of these mesenchymal cells from hepatic epithelium. In this short review, we describe (1) the principle mechanisms of hepatic fibrosis, (2) the cells which play a crucial role in hepatic fibrosis, and (3) the possible involvement of EMT in the process of hepatic fibrosis and carcinogenesis.
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PMID:Liver fibrosis: possible involvement of EMT. 1758 27

Non-invasive therapies for the treatment of hepatocellular carcinoma (HCC) would be of great benefit to public health. To this end, we have developed a platelet-derived growth factor-C (PDGF-C) transgenic (Tg) mouse model, which mimics many aspects of human liver carcinogenesis. Specifically, overexpression of PDGF-C results in liver fibrosis, which is preceded by activation and proliferation of hepatic stellate cells, and is followed by the development of dysplastic lesions and angiogenesis, and progression to HCCs by 8 months of age. Here, we show that PDGF-C overexpression induces the proliferation of endothelial-like cells that are present in tumors and adjacent non-neoplastic parenchyma. The protein tyrosine kinase inhibitor, imatinib (Gleevec), decreases the proliferation of non-parenchymal cells (NPC) in vitro and in vivo, with concomitant inhibition of Akt. In vivo treatment with imatinib also blocks the expression of CD34 in PDGF-C Tg mice. Decreased NPC proliferation and CD34 expression correlated with lower levels of active ERK1/2 and total levels of PDGF receptor alpha (PDGFRalpha). In summary, the small molecule inhibitor imatinib attenuates stromal cell proliferation in PDGF-C-induced HCC, which coincides with decreased expression of both CD34 and PDGFRalpha, and activated Akt. Our findings suggest that imatinib may be efficacious in the treatment of hepatocarcinogenesis, particularly when neovascularization is present.
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PMID:Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis. 1799 42

Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. In this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor beta1 (TGFbeta1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGFbeta1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGFbeta1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGFbeta1-reluctant cells. The TGFbeta1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGFbeta1 activity during liver fibrosis.
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PMID:Pleiotrophin inhibits transforming growth factor beta1-induced apoptosis in hepatoma cell lines. 1838 92


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