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Chronic Liver Diseases (chronic + liver_diseases)
Selected AbstractsPeroxisome proliferator-activated receptor-, as emerging target in liver diseaseDRUG DEVELOPMENT RESEARCH, Issue 2 2010Bernd Schnabl Abstract Liver fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) proteins that occurs in chronic liver disease of any origin, including nonalcoholic steatohepatitis (NASH), alcohol abuse, and viral hepatitis. Cirrhosis occurs with the development of regenerating nodules of hepatocytes and is a major health burden worldwide. Patients with decompensated liver cirrhosis have a poor prognosis, with liver transplantation often being necessary. The current treatment paradigm for patients with hepatic fibrosis is to treat the underlying liver disease. However, if this cannot be achieved, there are currently no effective antifibrotic treatments for patients with chronic liver diseases. With the advent of basic molecular technology providing insight into the mechanisms of the development of hepatic fibrosis, there is now an opportunity to develop therapeutic interventions for human clinical use. In this review, the function of peroxisome proliferator-activated receptor-, (PPAR ,) will be summarized with a special emphasis on ligand activation as potential use in liver disease. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc. [source] Hepatopulmonary Syndrome and Right Ventricular Diastolic Functions: An Echocardiographic ExaminationECHOCARDIOGRAPHY, Issue 4 2006Aziz Karabulut M.D. Aim: Liver functions are affected in the course of cardiac diseases, and similarly, liver diseases affect cardiac functions. Many studies in the literature have shown that left ventricular systolic and/or diastolic dysfunction may develop during chronic liver disease. However, there are limited studies investigating right ventricular functions during chronic liver diseases. Methods: A total of 84 patients who had no systolic and/or diastolic dysfunction in the left ventricle (LV) were evaluated; 46 patients with liver cirrhosis; 10 (21.74%) cirrhotic patients with hepatopulmonary syndrome (HPS) (group 1), 36 (78.26) cirrhotic patients without HPS (group 2), and 38 healthy individuals were treated as control. Results: Right ventricular diastolic dysfunction was determined in all patients of group 1 (100%), 26 of group 2 (72.22 %), and 4 of the controls (10.52%) (P < 0.05). Tricuspid deceleration time (dt) was significantly different between the groups (P < 0.05). In addition, right atrium (RA) diameters, right ventricle (RV) diameters, and RV wall thickness were significantly different between the groups (P < 0.05). Pulmonary artery pressure (P < 0.05) and pulmonary vascular resistance (P < 0.05) were also seen to be higher in group 1 than those in group 2 and control group. Conclusions: Right ventricular diastolic dysfunction rate is high in chronic liver diseases. In the presence of HPS, right ventricular diastolic dysfunction is more remarkable in patients than those without HPS. Right ventricular diastolic dysfunction may result in dilatation and hypertrophy in the right heart. [source] ADH1B*2 allele is protective against alcoholism but not chronic liver disease in the Hungarian populationADDICTION, Issue 5 2010Reka Toth ABSTRACT Background Standardized death rates from chronic liver diseases (CLDs) in Hungary are much higher than the European Union average. Carrying the alcohol dehydrogenase 1B 48His allele (rs1229984 or ADH1B*2) could decrease the risk of alcoholism, but with persistent drinking may confer a greater risk of CLDs. The aim of this study was to assess the prevalence of this polymorphism in the Hungarian population and its association with alcohol consumption and with CLDs. Methods and results A total of 278 cases with diagnosed CLDs and 752 controls without any alterations in liver function, all males aged 45,64, were screened for ADH1B Arg48His polymorphism. ADH1B*2 allele frequencies in controls and cases were 8.31% and 4.50%, respectively (,2 = 9.2; P = 0.01). Carrying the ADH1B*2 allele was associated with significantly lower odds ratio (OR) for drinking frequency (OR = 0.63; P = 0.003), the number of positive answers on CAGE (Cut-down, Annoyed, Guilt, Eye-opener) assessment (OR = 0.58; P = 0.005) and a positive CAGE status (OR = 0.55; P = 0.007). There was a significant association between ADH1B*2 and CLDs (OR = 0.50; P = 0.003), but it disappeared after adjusting for CAGE status and scores (OR = 0.67 P = 0.134; OR = 0.67 P = 0.148, respectively) and weakened after adjusting for drinking frequency (OR = 0.61; P = 0.045). Among heavy drinkers the presence of ADH1B*2 did not increase the risk of cirrhosis but there was a significant interaction between genotype and CAGE status (P = 0.003, P = 0.042), with ADH1B*2 conferring reduced risk of CLDs in CAGE negatives. Conclusion In Hungarians, the ADH1B 48His allele reduces the risk of alcoholism, but not the risk of chronic liver disease among heavy drinkers. [source] 13C-breath tests for clinical investigation of liver mitochondrial functionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2010Ignazio Grattagliano Eur J Clin Invest 2010; 40 (9): 843,850 Abstract Background, Mitochondria play a major role in cell energetic metabolism; therefore, mitochondrial dysfunction inevitably participates in or even determines the onset and progression of chronic liver diseases. The assessment of mitochondrial function in vivo, by providing more insight into the pathogenesis of liver diseases, would be a helpful tool to study specific hepatic functions and to develop rational diagnostic, prognostic and therapeutic strategies. Design, This review focuses on the utility of breath tests to assess mitochondrial function in humans and experimental animals. Results, The introduction in the clinical setting of specific breath tests may allow elegantly and noninvasively overcoming the difficulties caused by previous complex techniques and might provide clinically relevant information, i.e the effects of drugs on mitochondria. Substrates meeting this requirement are alpha-keto-isocaproic acid and methionine that are both decarboxylated by mitochondria. Long-and medium-chain fatty acids that are metabolized through the Krebs cycle, and benzoic acid which undergoes glycine conjugation, may also reflect the function of mitochondria. Conclusions, Breath tests to assess in vivo mitochondrial function in humans represent a potentially useful diagnostic and prognostic tool in clinical investigation. [source] Detection of Helicobacter ganmani -Like 16S rDNA in Pediatric Liver TissueHELICOBACTER, Issue 5 2004Vasundhara Tolia ABSTRACT Background., To determine the presence of Helicobacter species in the liver biopsy specimens from children with various chronic liver diseases as data in adult literature suggests a possible role of these bacteria in their pathogenesis. Materials and methods., Paraffin sections of 61 liver biopsies of pediatric patients with miscellaneous diseases and autopsy liver tissue from 10 control subjects with no evidence of preexisting liver disease were examined for the presence of Helicobacter species by a genus-specific seminested polymerase chain reaction (PCR) assay. PCR,products of positive samples were further characterized by denaturing gradient gel electrophoresis (DGGE) and DNA-sequence analysis. Based on those results, a seminested PCR assay for H. ganmani was developed and applied to the samples. Results., On analysis, 40/61 patient samples were positive in the genus-specific Helicobacter PCR and 4/10 from the control group. The nucleotide sequences of 16S rDNA fragments were 99,100% similar to mainly Helicobacter sp. ,liver' and H. ganmani. PCR-products similar to H. canis and H. bilis were also found. The 16S rDNAs of control specimens showed similarity to Helicobacter sp. ,liver'. In the H. ganmani -specific PCR analysis 19 patients, but none of the controls, were positive. Conclusions., Amplified Helicobacter 16S rDNAs were related to Helicobacter sp. ,liver' or H. ganmani in liver biopsy specimens of pediatric patients. The possible significance of Helicobacter species in pediatric liver diseases needs to be evaluated further in prospective studies. [source] CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice,HEPATOLOGY, Issue 4 2010Tomonori Aoyama Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4),induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor , (TNF-,); monocyte chemoattractant protein 1; macrophage inflammatory protein 1,; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-, and transforming growth factor , and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4 -treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010) [source] Tumor necrosis factor,like weak inducer of apoptosis is a mitogen for liver progenitor cells,,HEPATOLOGY, Issue 1 2010Janina E. E. Tirnitz-Parker Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor,like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin,positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NF,B) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NF,B subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NF,B-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (HEPATOLOGY 2010) [source] Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell,specific signal transducer and activator of transcription 3 gene knockout mice,HEPATOLOGY, Issue 5 2010Norio Horiguchi Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. Conclusion: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. Hepatology 2010 [source] CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis,HEPATOLOGY, Issue 4 2010Mirko Moreno Zaldivar Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4,/, and wild-type mice were subjected to two models of chronic liver injury (CCl4 and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus,induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl4 and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf -, [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4,/, mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8+ T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. Conclusion: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. (HEPATOLOGY 2010.) [source] Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis,,HEPATOLOGY, Issue 2 2009Yutaka Midorikawa Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region. Conclusion: 1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer. (HEPATOLOGY 2009.) [source] Racial differences in effectiveness of ,-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosisHEPATOLOGY, Issue 2 2002Mindie H. Nguyen ,-Fetoprotein (AFP) is frequently used as a diagnostic marker for hepatocellular carcinoma (HCC). Most available data concerning AFP come from studies of patients with chronic hepatitis B or other chronic liver diseases of mixed etiologies. Limited data concerning the diagnostic value of AFP for hepatitis C virus (HCV)-related HCC have to date come only from Asian and European studies, and results are conflicting. There may be significant differences in AFP levels depending on racial backgrounds and etiologies of primary liver disease. We conducted a multicenter, retrospective, case-control study of 163 HCC patients with HCV infection and 149 control patients with HCV-related cirrhosis. The positive likelihood ratios for AFP at 0 to 20, 21 to 50, 51 to 100, and 101 to 200 ng/mL were 0.46, 1.31, 1.15, and 6.90, respectively. No controls had AFP greater than 200 ng/mL. The sensitivity of AFP for the diagnosis of HCC in African Americans with HCV infection was lower than that of patients of all other ethnic groups combined (57.1% vs. 81.6% for AFP > 10 ng/mL, P = .02, and 42.9% vs. 66.0% for AFP > 20 ng/mL, P = .05). The area under the receiver operating characteristics curve was 0.81 for non-African Americans but only 0.56 for African Americans. In conclusion, AFP greater than 200 ng/mL can be used to confirm HCC in patients with HCV-related cirrhosis and a hepatic mass. However, AFP is insensitive for the diagnosis of HCC in African Americans. [source] Histological assessment of non-alcoholic fatty liver diseaseHISTOPATHOLOGY, Issue 5 2006S G Hübscher Non-alcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome, which is becoming an increasingly common cause of chronic liver disease. Histological changes typically mainly affect perivenular regions of the liver parenchyma and include an overlapping spectrum of steatosis, steatohepatitis and persinusoidal or pericellular fibrosis, in some cases leading to cirrhosis. Once cirrhosis has developed, typical hepatocellular changes are often no longer conspicuous, leading to such cases being mistakenly diagnosed as ,cryptogenic'. Portal inflammation, ductular reaction and periportal fibrosis can also be seen as part of the morphological spectrum of NAFLD, particularly in the paediatric population. Hepatocellular carcinoma has also been described as a complication of NAFLD-associated cirrhosis. NAFLD is also an important cofactor in other chronic liver diseases, especially hepatitis C. Histological assessments have an important role to play in the diagnosis and management of NAFLD. These include making the potentially important distinction between simple steatosis and steatohepatitis and providing pointers to the aetiology, including cases where a dual pathology exists. A number of systems have been devised for grading and staging the severity of fatty liver disease. These require further evaluation, but have a potentially important role to play in determining prognosis and monitoring therapeutic responses. [source] CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liverJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8a 2009Katia Bourd-Boittin Abstract Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. CX3CL1/fractalkine is a membrane-associated chemokine that requires step processing for chemotactic activity and has been recently implicated in liver disease. Here, we investigated the potential shedding activities involved in the release of the soluble chemotactic peptides from CX3CL1 in the injured liver. We showed an increased expression of the sheddases ADAM10 and ADAM17 in patients with chronic liver diseases that was associated with the severity of liver fibrosis. We demonstrated that hepatic stellate cells (HSC) were an important source of ADAM10 and ADAM17 and that treatment with the inflammatory cytokine inter-feron-, induced the expression of CX3CL1 and release of soluble peptides. This release was inhibited by the metalloproteinase inhibitor batimastat; however, ADAM10/ADAM17 inhibitor GW280264X only partially affected shedding activity. By using selective tissue metalloprotease inhibitors and overexpression analyses, we showed that CX3CL1 was mainly processed by matrix metalloproteinase (MMP)-2, a metalloprotease highly expressed by HSC. We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signalling pathway and promoted chemoattraction of monocytes in vitro. We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides, thereby facilitating recruitment of inflammatory cells and paracrine stimulation of HSC in chronic liver diseases. [source] Molecular, immunological and clinical properties of mutated hepatitis B virusesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2002C. Kreutz Abstract Hepatitis B virus (HBV) is at the origin of severe liver diseases like chronic active hepatitis, liver cirrhosis and hepatocellular carcinoma. There are some groups of patients with high risk of generation of HBV mutants: infected infants, immunosupressed individuals (including hemodialysis patients), patients treated with interferon and lamivudine for chronic HBV infection. These groups are the target for molecular investigations reviewed in this paper. The emergence of lamivudine- or other antiviral-resistant variants, rises concern regarding long term use of these drugs. Infection or immunization with one HBV subtype confers immunity to all subtypes. However, reinfection or reactivation of latent HBV infection with HBV mutants have been reported in patients undergoing transplant and those infected with HIV. Mutations of the viral genome which are not replicative incompetent can be selected in further course of infection or under prolonged antiviral treatment and might maintain the liver disease. Four open reading frames (ORF) which are called S-gene, C-gene, X-gene and P-gene were identified within the HBV genome. Mutations may affect each of the ORFs. Mutated S-genes were described to be responsible for HBV-infections in successfully vaccinated persons, mutated C-genes were found to provoke severe chronic liver diseases, mutated X-genes could cause serious medical problemes in blood donors by escaping the conventional test systems and mutated P-genes were considered to be the reason for chemotherapeutic drug resistance. This paper reviews molecular, immunological and clinical aspects of the HBV mutants. [source] Assessment of fibrosis in chronic liver diseasesJOURNAL OF DIGESTIVE DISEASES, Issue 1 2009Kun ZHOU The assessment of liver fibrosis provides useful information not only for diagnosis but also for therapeutic decisions. Although liver biopsy is the current gold standard for fibrosis assessment, it has some risks and limitations, including intra-observer and inter-observer variation, sampling error and variability. In recent years, many studies and great interest have been dedicated to the development of non-invasive tests to substitute a liver biopsy for fibrosis assessment and follow up. Advances in serological and radiological tests such as serum marker panels, transient elastography and their combinations can assess fibrosis accurately and reduce the need for a liver biopsy. But at present, all have failed to completely replace a liver biopsy because of their respective limitations and an imperfect gold standard used in current researches. The searching for an ideal surrogate is still in progress. [source] Bcl-2 overexpression in hepatic stellate cell line CFSC-2G, induces a pro-fibrotic stateJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2010Viridiana Y González-Puertos Abstract Background and Aim:, Development of hepatic fibrosis is a complex process that involves oxidative stress (OS) and an altered balance between pro- and anti-apoptotic molecules. Since Bcl-2 overexpression preserves viability against OS, our objective was to address the effect of Bcl-2 overexpression in the hepatic stellate cells (HSC) cell-line CFSC-2G under acetaldehyde and H2O2 challenge, and explore if it protects these cells against OS, induces replicative senescence and/or modify extracellular matrix (ECM) remodeling potential. Methods:, To induce Bcl-2 overexpression, HSC cell line CFSC-2G was transfected by lipofection technique. Green fluorescent protein-only CFSC-2G cells were used as a control. Cell survival after H2O2 treatment and total protein oxidation were assessed. To determine cell cycle arrest, proliferation-rate, DNA synthesis and senescence were assessed. Matrix metalloproteinases (MMP), tissue-inhibitor of MMP (TIMP), transglutaminases (TG) and smooth muscle a-actin (,-SMA) were evaluated by western blot in response to acetaldehyde treatment as markers of ECM remodeling capacity in addition to transforming growth factor-, (TGF-,) mRNA. Results:, Cells overexpressing Bcl-2 survived , 20% more than control cells when exposed to H2O2 and , 35% proteins were protected from oxidation, but Bcl-2 did not slow proliferation or induced senescence. Bcl-2 overexpression did not change ,-SMA levels, but it increased TIMP-1 (55%), tissue transglutaminases (tTG) (25%) and TGF-, mRNA (49%), when exposed to acetaldehyde, while MMP-13 content decreased (47%). Conclusions:, Bcl-2 overexpression protected HSC against oxidative stress but it did not induce replicative senescence. It increased TIMP-1, tTG and TGF-, mRNA levels and decreased MMP-13 content, suggesting that Bcl-2 overexpression may play a key role in the progression of fibrosis in chronic liver diseases. [source] Opioid receptor antagonist promotes angiogenesis in bile duct ligated ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2009Negar Faramarzi Abstract Background and Aim:, Angiogenesis, formation of new capillaries from existing vasculature, plays a pivotal role in different pathological states such as many chronic inflammatory diseases including the chronic liver diseases. There is increasing evidence demonstrating accumulation of endogenous opioids and their role in the pathophysiology and manifestations of cholestasis, the main feature of a number of chronic progressive liver diseases. Hence, we investigated the significance of endogenous opioids in angiogenesis in an experimental model of cholestasis. Methods:, Cholestasis was induced in male Sprague,Dawley rats by bile duct ligation and resection. Naltrexone, an opioid antagonist (20 mg/kg/day) was administered to cholestatic animals for 22 ± 1 days. The serial sections from liver tissue were stained with von Willebrand Factor antibody and micro-vessel density was assessed by calculating mean micro-vessel number in three hot spots high power microscopic fields. Results:, Naltrexone treatment in bile duct ligated rats led to a marked increase in the micro-vessel number (6.34 ± 0.21 vs 5.61 ± 0.22) (P < 0.05), which had already increased during cholestasis. Conclusion:, In order to clarify the impacts of opioid system blockade in cirrhosis, our findings demonstrate the promoting role of opioid antagonist in angiogenesis in a rat model of cholestasis. [source] Increasing trend of acute hepatitis A in north India: Need for identification of high-risk population for vaccinationJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2006Zahid Hussain Abstract Background and Aims:, Hepatitis A (HAV) is endemic in India and most of the population is infected asymptomatically in early childhood with lifelong immunity. Because of altered epidemiology and decreasing endemicity, the pattern of acute HAV infection is changing from asymptomatic childhood infection to an increased incidence of symptomatic disease in the 18,40 age group. The aims of the present study were to assess whether the proportion of adults with acute HAV infection has been increasing over the years and to analyze the seroprevalence of immunoglobulin G (IgG) anti-HAV antibodies in young adults above the age of 15 years as well as in cases of chronic liver disease. Methods:, Sera collected from 3495 patients with acute (1932) and chronic (1563) liver disease attending the Medical Outpatient Department of Lok Nayak Hospital during the previous five years (1999,2003) were tested for various serological markers of acute (HBsAg, HBcIgM, anti-HCV, HEV-IgM, and HAV-IgM) and chronic (HBsAg, HBcIgG, HBeAg, and anti-HCV) hepatitis. In addition, 500 normal healthy attendants of the patients above the age of 15 years were tested for IgG anti-HAV as controls. Results:, Of 1932 patients with acute viral hepatitis, 221 (11.4%) were positive for immunoglobulin M (IgM) anti-HAV. The patients who were IgM anti-HAV negative included hepatitis B (321 patients), C (39 patients), E (507 patients) and unclassified (844 patients). Although the frequency of HAV infection among children had increased (10.6% to 22.0%) in the 5-year period, the frequency of HAV infection among adults had also increased (3.4% to 12.3%) during the same period. A total of 300 patients with chronic liver diseases that were etiologically related to hepatitis B (169), C (73) or dual infection (10) and alcoholic liver injury (48) were tested for the presence of IgG anti-HAV antibody; 98% (294/300) were positive for the antibody. Conclusions:, Although universal vaccination against HAV is not currently indicated, selective vaccination of the high-risk population, based on their serological evidence of HAV antibody, would be a rational and cost-effective approach. [source] Value of regional cerebral blood flow in the evaluation of chronic liver disease and subclinical hepatic encephalopathyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2003YUSUF YAZGAN Abstract Aims:, Regional changes in cerebral blood flow in patients with chronic hepatitis, cirrhosis and subclinical hepatic encephalopathy were investigated in the present study using single photon emission computed tomography (SPECT). Methods:, Twenty patients with cirrhosis, 11 patients with chronic hepatitis, and nine healthy controls were included in the study. Cerebral SPECT were obtained for all patients. The percentages of cerebral blood flow of 14 regions to the cerebellar blood flow were determined. Only the patients with cirrhosis underwent psychometric evaluation: visual evoked potentials (VEP) measurements and electroencephalogram (EEG) recordings along with blood levels of albumin, bilirubin, and ammonia were measured and prothrombin time was determined in cirrhotic patients. These patients were classified according to the Child,Pugh classification. Results:, Among cirrhotic patients, six had abnormal results in VEP studies, 11 in psychometric tests and with six in EEG evaluation. Any abnormality in psychometric tests and/or VEP studies is taken as the main criterion; subclinical hepatic encephalopathy was detected in 12 of 20 patients. According to SPECT results in patients with subclinical encephalopathy, a statistically significant decrease in cerebral blood flow in right thalamus and nearly significant decrease in left thalamus were observed. Regional blood flow was significantly higher in the frontal lobes of patients with cirrhosis when compared with healthy controls. Similarly, cerebral blood flow in frontal and cingulate regions was significantly higher in patients with chronic hepatitis than in healthy controls. There was no relationship between cerebral blood flow and blood levels of ammonia or Child,Pugh score, in cirrhotic patients. Conclusion:, Significant changes in cerebral blood flow may be present in chronic liver diseases and the authors suggest that the measurement of changes in cerebral blood flow might be useful in detecting subclinical hepatic encephalopathy. [source] Incidence of Sjögren's syndrome in Japanese patients with hepatitis C virus infectionJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2003YUMIKO NAGAO Abstract Background and Aim: Hepatitis viruses induce not only chronic liver diseases but also the impairment of other organs and tissues as extrahepatic manifestations. In particular, hepatitis C virus (HCV) is involved in various extrahepatic manifestations. The purpose of the present study was to evaluate Sjögren's syndrome (SS) and lichen planus (LP) involvement, which are various extrahepatic manifestations in patients with liver diseases related to hepatitis B virus (HBV) or HCV. Methods: We examined a total of 110 Japanese patients with chronic liver disease: 29 with HBV infections and 81 HCV infections. Results: The prevalence of SS according to European and Japanese criteria in patients with chronic HCV infection was significantly higher than in patients with chronic HBV infection (European criteria: 25.9 vs 3.4%; P < 0.05, Japanese criteria: 21.0 vs 3.4%; P = 0.05). Lichen planus was observed in one (3.4%) of 29 patients with chronic HBV infection, and in 11 (13.6%) of 81 patients with chronic HCV infection. Simultaneously combined LP and SS occurred in 8.6% (seven of 81) of patients with HCV infection, but in none with HBV infection. Conclusions: Clinicians should routinely follow the HCV-infected patients, paying sufficient attention to the presence of SS and LP, and they should also carefully monitor their prognosis. [source] Perihepatic lymphadenopathy in chronic liver diseasesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2000Hiromasa Ishii No abstract is available for this article. [source] Treatment of chronic liver diseases with traditional Chinese medicineJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2000Bao-En Wang Traditional Chinese medicine is still being extensively used for treatment of liver disease in China. The anti-viral herbs, Phyllanthus amarus, P. niruri and P. urninaria, and Oxymatrine extracted from Sophora flavecientis and S. subprostratae, have been shown to have a remarkable HBV suppressing effect with a serum conversion rate for HBeAg and HBV DNA around 45%, similar to that of IFN-,. The anti-inflammatory compound, Stronger NeoMinophagen C (SNMC), is a Japanese preparation of glycerrhizin, extracted from Glyceriza glabra, which has shown an effective rate of ALT and AST normalization and reduction to < 60 U/L in 65.6% and 73.5% of patients. Compound 861, made of 10 herbs with Salvia miltiorrhiza as its chief component, has been shown experimentally to be effective in suppressing fibrogenesis, enhancing collagen degradation, and inhibiting TIMP expression. Clinically, an open trial of 2000 patients showed improvement of symptoms in 83% and normalization of serum ALT in 82%. In a controlled study of 107 patients with HBV-related diseases, double liver biopsies showed that the fibrosis reversal rate after 6 months treatment with Cpd 861 was 78% in S2, 82% in S3 (precirrhotic stage) and 75% in S4 (early cirrhosis), as assessed by Scheuer's and Chevallier's criterion. In conclusion, traditional Chinese medicine has great potential in the treatment of chronic hepatitis B. [source] Circulating adiponectin reflects severity of liver disease but not insulin sensitivity in liver cirrhosisJOURNAL OF INTERNAL MEDICINE, Issue 3 2005S. KASER Abstract. Background., The adipocytokine adiponectin has been proposed to play important roles in the regulation of energy homeostasis, insulin sensitivity and shows anti-inflammatory properties. Aim., In this study we investigated the role of circulating adiponectin in different chronic liver diseases, its regulation by systemic anti-tumour necrosis factor (TNF)- , treatment and its hepatic metabolism. Patients and methods., Plasma adiponectin levels were determined in 87 patients with liver cirrhosis of different aetiologies, seven patients with alcoholic steatohepatitis undergoing systemic anti-TNF- , treatment, in 11 patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt implantation and in 21 healthy controls. Results., Adiponectin levels were significantly higher in all subjects with liver cirrhosis of different aetiologies when compared with healthy controls and increased dependent on Child-Pugh classification. In subjects with alcoholic steatohepatitis, systemic anti-TNF- , treatment caused a significant decrease in circulating adiponectin. Adiponectin concentrations were similar in portal, hepatic and peripheral veins. No correlation between adiponectin levels and insulin resistance was found in any patient group. Conclusions., Our data suggest that circulating adiponectin is increased in liver cirrhosis independent of the aetiology of liver disease. We suggest that high adiponectin levels in chronic liver disease might reflect one of the body's anti-inflammatory mechanisms in chronic liver diseases. [source] Chronic Alcohol Consumption Is Associated With an Increased Cytotoxic Profile of Circulating Lymphocytes That May Be Related With the Development of Liver InjuryALCOHOLISM, Issue 5 2010Francisco Javier Laso Background:, Apoptosis has recently emerged as a key component of acute and chronic liver diseases and it could be related to alcoholic liver disease. In the present study, we attempted to analyze the cytotoxic profile of circulating lymphocytes in chronic alcoholic patients grouped according to ethanol intake status and presence of liver disease. Methods:, We investigate the phenotypic and functional behavior of different compartments of peripheral blood (PB) cytotoxic T and natural killer (NK) cells in chronic alcoholic patients without liver disease and active ethanol intake (AWLD group; n = 22), and in subjects with alcohol liver cirrhosis (ALC group; n = 22). Results:, AWLD patients showed an expansion of both CD4+/CD8+ cytotoxic T cells and NK/T cells, in association with an enhanced cytolytic activity against K562 cells and a higher ability to induce in vitro expression of the pro-apoptotic protein APO2.7 in HepG2 cells. Conversely, ethanol intake in ALC patients was associated with decreased NK cell numbers, a reduced cytotoxic activity against K562 cells without significant changes in the expression of APO2.7, and a pro-fibrotic profile of cytokine secretion. Conclusions:, Overall, our results suggest that alcoholic patients display different phenotypical and functional changes in circulating PB cytotoxic lymphocytes according to the presence of alcoholic liver disease, which could be related to the development and progress of liver injury. [source] NeoHepatocytes From Alcoholics and Controls Express Hepatocyte Markers and Display Reduced Fibrogenic TGF-,/Smad3 Signaling: Advantage for Cell Transplantation?ALCOHOLISM, Issue 4 2010Sabrina Ehnert Background:, Liver transplantation is the only definitive treatment for end stage liver disease. Donor organ scarcity raises a growing interest in new therapeutic options. Recently, we have shown that injection of monocyte-derived NeoHepatocytes can increase survival in rats with extended liver resection. In order to apply this technology in humans with chronic liver diseases in an autologous setting, we generated NeoHepatocytes from patients with alcoholic liver disease and healthy controls and compared those to human hepatocytes. Methods:, We generated NeoHepatocytes from alcoholics with Child A and B cirrhosis and healthy controls. Hepatocytes marker expression and transforming growth factor (TGF)-, signaling was investigated by RT-PCR, Western blot, immunofluorescent staining, and adenoviral reporter assays. Glucose and urea was measured photometrically. Phase I and II enzyme activities were measured using fluorogenic substrates. Neutral lipids were visualized by Oil Red O staining. Results:, There was no significant difference in generation and yield of NeoHepatocytes from alcoholics and controls. Hepatocyte markers, e.g., cytokeratin18 and alcohol dehydrogenase 1, increased significantly throughout differentiation. Glucose and urea production did not differ between alcoholics and controls and was comparable to human hepatocytes. During differentiation, phase I and II enzyme activities increased, however remained significantly lower than in human hepatocytes. Fat accumulation was induced by treatment with insulin, TGF-, and ethanol only in differentiated cells and hepatocytes. TGF-, signaling, via Smad transcription factors, critically required for progression of chronic liver disease, was comparable among the investigated cell types, merely expression of Smad1 and -3 was reduced (,30 and ,60%) in monocytes, programmable cells of monocytic origin, and NeoHepatocytes. Subsequently, expression of TGF-, regulated pro-fibrogenic genes, e.g., connective tissue growth factor and fibronectin was reduced. Conclusions:, Generation of NeoHepatocytes from alcoholics, displaying several features of human hepatocytes, offers new perspectives for cell therapeutic approaches, as cells can be obtained repeatedly in a noninvasive manner. Furthermore, the autologous setting reduces the need for immunosuppressants, which may support recovery of patients which are declined for liver transplantation. [source] Lichen planus and leukocytoclastic vasculitis induced by interferon alpha-2b in a subject with HCV-related chronic active hepatitisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2 2003JM De Sousa Pinto ABSTRACT Lichen planus (LP) has been reported in association with chronic active hepatitis, primary biliary cirrhosis and other chronic liver diseases. The occurrence of LP in persons with hepatitis C virus (HCV) was reported by Robert et al., and the possible relationship between LP and hepatitis virus has also been supported by cases of LP following hepatitis B vaccination. Exacerbation or appearance of LP during the treatment of chronic hepatitis C, lymphoproliferative diseases and melanoma with alpha-interferon (IFN-,) and improvement of these diseases after discontinuation of this drug indicate that IFN-, may possibly induce LP. We present a case of cutaneo-mucous LP in a woman with chronic active hepatitis treated with IFN-, and in whom local leukocytoclastic vasculitis was induced by the intradermal injection of a very low dose of IFN-,. [source] Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor , a randomized placebo-controlled study in patients with chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2010M. L. SHIFFMAN Aliment Pharmacol Ther,31, 969,978 Summary Background, Elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) reflect hepatocellular injury in patients with chronic hepatitis C virus (HCV). Increased apoptosis and activated caspases are present in these patients. PF-03491390 inhibits multiple caspases and lowers serum AST and ALT levels in patients with chronic liver diseases. Aim, To determine if treatment with an oral pancaspase inhibitor could reduce serum AST and ALT in patients with HCV. Methods, Double-blind, randomized, placebo-controlled, parallel-dose study in 204 patients treated with placebo or PF-03491390 (5, 25 or 50 mg) orally twice daily (b.d.) for up to 12 weeks. Serum AST and ALT were monitored weekly. Results, Significant reductions in serum AST and ALT were observed within 1 week of initiating PF-03491390 in all treatment groups (P < 0.0001). These reductions in AST and ALT were maintained throughout the 12 week treatment period and returned to baseline levels when PF-03491390 was discontinued. Increasing the dose did not further lower AST or ALT. The most frequently reported adverse events were headache and fatigue. Conclusion, PF-03491390 significantly reduced serum AST and ALT levels in patients with chronic HCV, and was well tolerated over 12 weeks. [source] Predictors of health-related quality of life in patients with chronic liver diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009A. AFENDY Summary Background, Patient-reported outcomes like health-related quality of life (HRQL) have become increasingly important for full assessment of patients with chronic liver diseases (CLD). Aim, To explore the relative impact of different types of liver disease on HRQL as well as predictors of HRQL domains in CLD. Methods, Our HRQL databases with Short-Form 36 (SF-36) data were used. Scores for each of SF-36 scales (PF , physical functioning, RP , role functioning, BP , bodily pain, GH , general health, VT , vitality, SF , social functioning, RE , role emotional and MH , mental health, MCS , mental component score, PCS , physical component score) were compared between different types of CLD as well as other variables. Results, Complete data were available for 1103 CLD patients. Demographic and clinical data included: age 54.2 ± 12.0 years, 40% female, 761 (69%) with cirrhosis. Analysis revealed that age correlated significantly (P < 0.05) with worsening HRQL on every scale of the SF-36. Female patients had more HRQL impairments in PF, RP, BP, GH, VT and MH scales of SF-36 (, scale score: 6.6,10.7, P < 0.05). Furthermore, cirrhotic patients had more impairment of HRQL in every scale of SF-36 (, scale score: 6.6,43.0, P < 0.05). In terms of diagnostic groups, non-alcoholic fatty liver disease patients showed more impairment of HRQL. Conclusions, Analysis of this large CLD cohort suggests that a number of important clinicodemographic factors are associated with HRQL impairment. These findings contribute to the full understanding of the total impact of CLD on patients' health. [source] Association of antibodies to hepatitis C virus glycoproteins 1 and 2 (anti-E1E2) with HCV diseaseJOURNAL OF VIRAL HEPATITIS, Issue 5 2008M. R. B. Hamed Summary., Hepatitis C virus (HCV) causes acute and chronic liver diseases in humans. Its two envelope glycoproteins, E1 and E2, provide a target for host immune recognition. HCV genotypes are classified into six genetic groups. To study the role of anti-HCV E1 and E2 (anti-E1E2) in HCV disease, the correlation between antibody level and viral load, genotype, disease severity and response to treatment was investigated. The levels of antibodies to HCV glycoproteins E1 and E2 antibodies were evaluated in 230 sera of patients with chronic hepatitis C by enzyme-linked immunosorbent assay. The antigens used were recombinant HCV glycoproteins derived from genotype 1 (H77c) and genotype 3 (UKN3A1.28). Seroreactivity was greater when sera were tested against antigen derived from their homologous genotype than against heterologous antigen. Reactivity against UKN3A1.28 in sera from patients infected with genotype 3 was significantly higher than corresponding reactivity between patients infected with genotype 1 and H77c. The seroreactivity was inversely proportional to the viral load and to the degree of liver fibrosis. The pre-treatment level of anti-E1E2 was higher in sustained responders to combination therapy. These results demonstrate that seroreactivity against E1E2 depends upon the genotypic origin of the E1E2 antigens and the infecting genotype, and suggest a possible protective effect of anti-E1E2 against disease progression. [source] Transient elastography: a valid alternative to biopsy in patients with chronic liver diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2006E. GÓMEZ-DOMÍNGUEZ Summary Background Transient elastography is a novel and non-invasive technique for the evaluation of fibrosis in chronic liver disease. Few studies that exist value the efficacy of transient elastography, mainly in hepatitis C virus-infected patients. Aim To evaluate the effectiveness, objectivity, reproducibility and safety of this technique. Methods We included 103 consecutive patients who underwent a liver biopsy in the last 48 months with a wide spectrum of chronic liver diseases. Median stiffness value (expressed as kilopascals , kPa) was kept as representative of the liver elastic modulus. All biopsy specimens were analysed by the same pathologist according to the METAVIR scoring system. Results Median value of stiffness in patients with mild or moderate fibrosis (FI and FII), and severe fibrosis or cirrhosis (FIII and FIV) was of 7, 4 ± 5 and 16, 4 ± 10 kPa, respectively, with a significant difference between them (P < 0.05). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut-off values for each group. Conclusions We found a positive correlation between the liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease aetiology. Transient elastography is an easy, quick to perform and safe non-invasive procedure, reliable for assessing liver fibrosis. [source] | |||||||||||||||||||||||||||||||