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)

Surgery is often not a treatment option in patients with hepatocellular carcinoma with the numerous limitations of liver transplantation or surgical resection due to coexisting cirrhosis in the later case. Non-surgical treatments deal with 3 types of methods: local ablation with curative purpose, transarterial treatments with many technical variants and systemic treatment. Local treatments rely on chemical or thermic agents to achieve ablation of liver lesions, which not exceed initially 3 cm in diameter. The use of radiofrequency ablation allows now larger limits. Intra-arterial treatment usually combines intra-arterial chemotherapy with embolisation of hepatic artery in a procedure called chemoembolisation. Its antitumoral effect mainly due to ischemia is well documented but the influence on survival remains controversial. Finally systemic treatments have yet to be demonstrated useful: new agents and new randomised trials are still needed.
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PMID:[Non-surgical treatment of hepatocellular carcinoma. An overview]. 1623 41

The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1alpha. Since TNF and FasL-induced hepatocyte apoptosis is implicated in a wide range of liver diseases, including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-XL or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c-based method useful for the diagnosis and monitoring of fulminant hepatitis.
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PMID:Apoptosis in liver diseases--detection and therapeutic applications. 1625 9

Oxidative stress is implicated in the pathogenesis of hepatic ischemia-reperfusion injury, a major determinant of initial poor graft function (IPGF) after orthotopic liver transplantation (OLT). We prospectively investigated the association between the recipient plasma preoperative oxidative stress and the occurrence of IPGF after deceased-donor OLT and indirectly studied the source-hepatic or extra-hepatic-of systemic oxidative stress in vivo in cirrhosis. We used a recently developed specific and sensitive mass spectrometry assay to measure 7beta-hydroxycholesterol and 7-ketocholesterol (oxysterols), markers of oxidative stress, in biological matrices. At univariate analysis, preoperative recipient 7beta-hydroxycholesterol plasma concentration was significantly higher in transplants with subsequent IPGF (n = 9) compared with those with initial good graft function (IGGF; n = 23) [mean +/- SD: 30.63 +/- 26.42 and 11.57 +/- 15.76 ng/mL, respectively] (P = 0.017). In a logistic regression model, which included also the Model for End-Stage Liver Disease (MELD) score, 7beta-hydroxycholesterol plasma concentration was an independent predictor of IPGF with an odds ratio of 1.17 (95% CI, 1.02-1.33, P = 0.028). Patients with cirrhosis (n = 32) had increased oxysterol plasma levels compared with healthy controls (n = 49); livers with cirrhosis (n = 21), however, had oxysterol content comparable with normal livers obtained from organ donors (n = 19). Oxysterols persisted elevated in plasma 1 month after OLT (n = 23). In conclusion, cirrhosis presents upregulated systemic oxidative stress likely of extrahepatic source that is associated with graft failure after OLT.
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PMID:High preoperative recipient plasma 7beta-hydroxycholesterol is associated with initial poor graft function after liver transplantation. 1625 53

Chronic ethanol-induced liver injury follows a typical progression from its earliest stage of steatosis to more advanced injury, characterized by the development of inflammation, hepatocyte necrosis/apoptosis, fibrosis and finally cirrhosis. Kupffer cells, the resident macrophage in the liver, play a critical role in the progression of liver injury. Increased exposure of Kupffer cells to lipopolysaccharide (LPS) during chronic ethanol exposure leads to the production of a number of inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha). Recent evidence indicates that in addition to increased exposure to LPS, Kupffer cells also develop an enhanced sensitivity to LPS after chronic ethanol feeding. We have recently identified early growth response-1 (Egr-1), an immediate-early gene transcription factor, as an important contributor to increased LPS-stimulated TNF-alpha secretion by Kupffer cells after chronic ethanol exposure. In other models of tissue injury, such as ischemia-reperfusion in the lung, Egr-1 acts as a coordinator of the complex response to stress. Here we review the literature regarding the role of EGR-1 in regulation of a number of genes implicated in each of the stages of chronic ethanol-induced liver injury. In addition to the critical role of Egr-1 in generating maximal LPS-stimulated TNF-alpha expression, Egr-1 also controls the expression of a number of inflammatory mediators, including intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2, as well as genes contributing to fibrosis, such as transforming growth factor (TFG)-beta1, platelet-derived growth factor PDGF-A chain and fibroblast growth factor (FGF). Understanding the contribution of Egr-1 to the expression of genes involved in the development of chronic ethanol-induced liver injury may lead to the development of improved therapies designed to prevent and/or reverse alcohol-induced liver injury.
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PMID:Ethanol-induced liver injury: potential roles for egr-1. 1634

Roux-en-Y hepatojejunostomy is the procedure of choice for biliary reconstruction after complex iatrogenic injury that is usually associated with vascular injuries and concomitant ischemia of the ducts. To avoid the ischemic component, our group routinely performs a high repair to assure an anastomosis in noninflamed, nonscarred, and nonischemic ducts. If the duct bifurcation is preserved, the Hepp-Couinaud approach for reconstruction is an excellent choice. Partial liver resection of segments IV and V allows adequate exposure of the bile duct at its bifurcation with an anterior approach of the ducts (therefore not jeopardizing the circulation), allowing a high quality anastomosis. Long-term results of bile duct reconstruction using this approach are described. Two hundred eighty-five bile duct reconstructions were done between 1989 and 2004 in a tertiary care university hospital. The first partial-segment IV resection was done in 1994; 94 cases have been reconstructed since then using this approach. All of them had a complex injury (Strasberg E1-E5), and although in many cases the bifurcation was preserved (E1-E3), a high bilioenteric anastomosis was done to facilitate the reconstruction. In 70 cases, the bifurcation was identified, and in the 24 in which the confluence was not preserved, the right and left ducts were found except in one case. In three patients, the right duct was found unsuitable for anastomosis, and a liver resection was done. In the remaining 21, an anastomosis was done using a stent (transhepatic, transanastomotic) through the right duct. According to Lillemoe's criteria, 86 cases had good results (91%). In four of the eight remaining patients, there was the need to operate again due to the presence of an obstruction and/or cholangitis. In the rest, radiological instrumentation was done. Four of these cases have developed secondary biliary cirrhosis, two of which have died while waiting for a liver transplant, four and six years after reconstruction. Partial segments IV and V resection allows adequate exposure of the confluence and the isolated left or right hepatic ducts. Anterior exposure of the ducts allows an anastomosis in well-preserved, nonischemic, nonscarred, or noninflamed ducts. Parenchyma removal also allows the free placement of the jejunal limb, without external compression and tension, obtaining a high quality anastomosis with excellent long-term results.
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PMID:Long-term evaluation of biliary reconstruction after partial resection of segments IV and V in iatrogenic injuries. 1636 94

Hepatic fibrosis is a wound healing response, involving pathways of inflammation and fibrogenesis. In response to various insults, such as alcohol, ischemia, viral agents, and medications or hepatotoxins, hepatocyte damage will cause the release of cytokines and other soluble factors by Kupffer cells and other cell types in the liver. These factors lead to activation of hepatic stellate cells, which synthesize large amounts of extracellular matrix components. With chronic injury and fibrosis, liver architecture and metabolism are disrupted, eventually manifesting as cirrhosis and its complications. In addition to eliminating etiology, such as antiviral therapy and pharmacological intervention, it is encouraging that novel strategies are being developed to directly address hepatic injury and fibrosis at the subcellular and molecular levels. With improvement in understanding these mechanisms and pathways, key steps in injury, signaling, activation, and gene expression are being targeted by molecular modalities and other molecular or gene therapy approaches. This article intends to provide an update in terms of the current status of molecular therapy for hepatic injury and fibrosis and how far we are from clinical utilization of these new therapeutic modalities.
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PMID:Molecular therapy for hepatic injury and fibrosis: where are we? 1648 61

Hepaticojejunostomy is a good alternative technique for biliary reconstruction in liver transplantation. Among 517 liver transplants performed between March 1992 and July 2005, 33 involved hepaticojejunostomy, namely, 18 men and 12 women of average age: 44.8 years. The main cause for this technique was retransplant (n = 10), secondary biliary cirrhosis (n = 5), alcoholic cirrhosis (n = 5), HCV cirrhosis (n = 2), primary biliary cirrhosis (n = 1), cryptogenic cirrhosis (n = 1), sclerosing cholangitis (n = 3), fulminant liver failure (n = 1), autoimmune cirrhosis (n = 1), and insulinoma metastasis (n = 1). Choledochojejunostomy was performed for all Roux-en-Y loops, with an average cold ischemia time of 361.16 minutes (180-780). The biliary complications were biliary fistula in four cases (13.3%), including two who required surgery; stenosis of the anastomosis in two cases (6.6%) including one diagnosed by HIDA that resolved with medical treatment and the other, diagnosed by cholangio-MRI, requiring a new hepaticojejunostomy; and biliary peritonitis in three cases (10%), all of whom required surgery. The vascular complications were thrombosis of the hepatic artery (n = 1), which required retransplantation, and pseudoaneurysm of hepatic artery (n = 1). No biliary complications occurred. The 6-month patient survival was 80% and the 6-month graft survival was 77%; no patient died due to biliary complications. Hepaticojejunostomy is a technique with higher morbidity than choledocho-choledochostomy, but it is the best alternative when the latter is not possible.
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PMID:Biliodigestive anastomosis in liver transplantation: review of 13 years. 1709 70

Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of alpha-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.
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PMID:Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. 1726 5

Spontaneous regression of a malignant tumor is an exceptional phenomenon. A 56-year-old woman with liver cirrhosis related to chronic hepatitis C presented with a liver tumor. Partial regression of a hepatocellular carcinoma was diagnosed by imaging studies that showed progressive diminution of the size of the tumor and changes in the tumor markers. However, because of the persistence of the tumor and uncertainty in the diagnosis we recommended surgery. A hepatectomy was performed and a hepatocellular carcinoma moderately differentiated was found. The patient is now doing well and without any evidence of recurrence at 25 months after surgery. We found 61 case reports that have been published from 1982 to September 2006, with apparently spontaneous regression of hepatocellular carcinoma. The precise mechanism regarding the spontaneous regression of this tumor is not fully understood, either ischemia due to rapid growth of the neoplasia or particular inflammatory and immunologic mechanisms may be involved in the regression of the hepatocellular carcinoma.
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PMID:Spontaneous partial regression of hepatocellular carcinoma in a cirrhotic patient. 1729 33

The hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha are structurally similar as regards their DNA-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1 alpha(-/-) and hif-2 alpha(-/-) mice, in their functions. This implies that HIF-1 alpha and HIF-2 alpha may have unique target genes. To address this discrepancy and identify HIF-2 alpha-specific target genes, we performed yeast two-hybrid analysis and identified the tumor suppressor Int6/eIF3e/p48 as a novel target gene product involved in HIF-2 alpha regulation. The int6 gene was first identified from a screen in which the mouse mammary tumor virus was employed as an insertional mutagen to identify genes whose functions are critical for breast tumor formation. Here, by using two-hybrid analysis, immunoprecipitation in mammalian cells, and HRE-reporter assays, we report the specific interaction of HIF-2 alpha (but not HIF-1 alpha or HIF-3 alpha) with Int6. The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2 alpha degradation. This degradation was clearly observed in renal cell carcinoma 786-O cells, and was found to be both hypoxia- and pVHL-independent. Furthermore, Int6 protein knockdown by int6-siRNA vectors or the dominant-negative mutant Int6-Delta C increased endogenous HIF-2 alpha expression, even under normoxia, and induced sets of critical angiogenic factors comprising vascular endoplasmic growth factor, angiopoietin, and basic fibroblast growth factor mRNA. These results indicate that Int6 is a novel and critical determinant of HIF-2 alpha-dependent angiogenesis as well as cancer formation, and that int6-siRNA transfer may be an effective therapeutic strategy in pathological conditions such as heart and brain ischemia, hepatic cirrhosis, and obstructive vessel diseases.
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PMID:Mammalian tumor suppressor Int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent regulation. 1732 24


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