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1.
PLoS One ; 12(7): e0180927, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704535

RESUMO

INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.


Assuntos
Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , 2',5'-Oligoadenilato Sintetase/genética , Adulto , Idoso , Aspartato Aminotransferases/sangue , Endorribonucleases/genética , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Humanos , Interferons , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de Citocina/genética , TYK2 Quinase/genética
2.
Liver Int ; 37(8): 1148-1156, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28027429

RESUMO

BACKGROUND & AIMS: Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied. METHODS: Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined. RESULTS: Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV. CONCLUSIONS: Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.


Assuntos
Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Hepacivirus/fisiologia , Hepatite C Crônica/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular , Progressão da Doença , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Replicon , Transdução de Sinais , Proteínas Virais/metabolismo
3.
J Hepatol ; 66(3): 485-493, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27780714

RESUMO

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.


Assuntos
Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/complicações , Adulto , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Resposta Viral Sustentada
4.
World J Gastroenterol ; 22(44): 9744-9751, 2016 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-27956798

RESUMO

AIM: To evaluate the efficacy of peripheral blood concentrations of angiopoietins (Ang) as cirrhosis biomarkers of chronic hepatitis C (CHC). METHODS: Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays (ELISA) in samples from 179 cirrhotic and non-cirrhotic CHC patients, classified according to the METAVIR system. Groups were compared by non-parametric Mann-Whitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics (AUC-ROC). RESULTS: Peripheral blood concentrations of Ang1 and Ang2 in CHC patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non-cirrhotic (P < 0.0001), Ang2 was significantly increased as CHC progressed to the end stage of liver disease (P < 0.0001). Consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis (P < 0.0001). Interestingly, the individual performance of each angiopoietin for the diagnosis of cirrhosis reached notable AUC-ROC values (above 0.7, both), but the Ang2/Ang1 ratio was much better (AUC-ROC = 0.810) and displayed outstanding values of sensitivity (71%), specificity (84%) and accuracy (82.1%) at the optimal cut-off (10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in CHC. CONCLUSION: Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target.


Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Hepatite C Crônica/complicações , Cirrose Hepática/sangue , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite C Crônica/diagnóstico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto Jovem
6.
J Clin Microbiol ; 53(1): 219-26, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25378574

RESUMO

Hepatitis C virus (HCV) is classified into seven major genotypes and 67 subtypes. Recent studies have shown that in HCV genotype 1-infected patients, response rates to regimens containing direct-acting antivirals (DAAs) are subtype dependent. Currently available genotyping methods have limited subtyping accuracy. We have evaluated the performance of a deep-sequencing-based HCV subtyping assay, developed for the 454/GS-Junior platform, in comparison with those of two commercial assays (Versant HCV genotype 2.0 and Abbott Real-time HCV Genotype II) and using direct NS5B sequencing as a gold standard (direct sequencing), in 114 clinical specimens previously tested by first-generation hybridization assay (82 genotype 1 and 32 with uninterpretable results). Phylogenetic analysis of deep-sequencing reads matched subtype 1 calling by population Sanger sequencing (69% 1b, 31% 1a) in 81 specimens and identified a mixed-subtype infection (1b/3a/1a) in one sample. Similarly, among the 32 previously indeterminate specimens, identical genotype and subtype results were obtained by direct and deep sequencing in all but four samples with dual infection. In contrast, both Versant HCV Genotype 2.0 and Abbott Real-time HCV Genotype II failed subtype 1 calling in 13 (16%) samples each and were unable to identify the HCV genotype and/or subtype in more than half of the non-genotype 1 samples. We concluded that deep sequencing is more efficient for HCV subtyping than currently available methods and allows qualitative identification of mixed infections and may be more helpful with respect to informing treatment strategies with new DAA-containing regimens across all HCV subtypes.


Assuntos
Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Filogenia , Proteínas não Estruturais Virais/genética , Técnicas de Genotipagem , Hepatite C/diagnóstico , Humanos , Kit de Reagentes para Diagnóstico
7.
PLoS One ; 9(10): e106958, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25302785

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD. METHODS: Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined. RESULTS: Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC. CONCLUSIONS: These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.


Assuntos
Hepacivirus/fisiologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/virologia , Hepatite C Crônica/patologia , Receptor TIE-2/antagonistas & inibidores , Anticorpos Neutralizantes/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/patologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/enzimologia , Humanos , Fígado/patologia , Fígado/virologia , Inibidores de Proteínas Quinases/farmacologia , Receptor TIE-2/análise
10.
Rev Esp Enferm Dig ; 105(7): 409-20, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24206551

RESUMO

Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of alterations that go from simple steatosis to steatohepatitis and cirrhosis. Type 2 diabetes mellitus (DM-2) and obesity are the principle factors associated to NAFLD. A 20-30 % prevalence in general population has been described. The survival of this type of patient is lower than the general population's, showing a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear, but we know the intervention of different factors that produce fatty-acid accumulation in hepatic parenchyma, causing oxidative stress, oxygen-free radicals and the synthesis of an inflammatory cascade, that determine the progression of this disease from steatosis up to advanced fibrosis.The diagnostic gold-standard is still the liver biopsy, even though the development of newer non-invasive techniques, like serological and imaging (radiology), have opened a new field for research that allows bloodless testing of these patients and better study of the natural history of this disease. Nowadays, there is still no specific treatment for NAFLD. The development of healthy life habits and moderate exercise continue to be the pillars of treatment. Different pharmacological approaches have been studied and applied, such as the control of insulin resistance, lowering cholesterol levels, antioxidants, and other alternatives in experimental trials.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia
11.
Rev. esp. enferm. dig ; 105(7): 409-420, ago. 2013. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-116836

RESUMO

La enfermedad por hígado graso no alcohólica (EHGNA) comprende un amplio abanico de alteraciones que va desde la esteatosis simple hasta la esteatohepatitis y la cirrosis. La diabetes mellitus tipo 2 y la obesidad son los principales factores asociados a la EHGNA. Se ha descrito una prevalencia en la población general de entre el 20-30 %. La supervivencia de estos enfermos es menor que la población general, presentando una mayor incidencia de complicaciones hepáticas y cardiovasculares. La etiopatogenia es desconocida en parte pero se conoce la intervención de diferentes factores que provocan la acumulación de ácidos grasos en el parénquima hepático, produciendo una situación de estrés oxidativo, la formación de radicales libres de oxígeno y la síntesis de una cascada inflamatoria de citocinas que determinan la progresión de la enfermedad desde esteatosis hasta fibrosis avanzada. La prueba diagnóstica de elección continúa siendo la biopsia hepática, si bien el desarrollo de diferentes técnicas no invasivas, tanto serológicas como de imagen, ha abierto un nuevo campo de investigación que permite una evaluación incruenta de estos pacientes y un mejor estudio de la historia natural de la enfermedad. En la actualidad no existe un tratamiento específico. El desarrollo de hábitos de vida saludables y el ejercicio físico moderado continúan siendo los pilares básicos. Se han investigado y aplicado diferentes aproximaciones farmacológicas incluyendo el control de la resistencia a la insulina, hipolipemiantes, antioxidantes y otras alternativas en vía experimental (AU)


Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of alterations that go from simple steatosis to steatohepatitis and cirrhosis. Type 2 diabetes mellitus (DM-2) and obesity are the principle factors associated to NAFLD. A 20-30 % prevalence in general population has been described. The survival of this type of patient is lower than the general population’s, showing a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear, but we know the intervention of different factors that produce fatty-acid accumulation in hepatic parenchyma, causing oxidative stress, oxygen-free radicals and the synthesis of an inflammatory cascade, that determine the progression of this disease from steatosis up to advanced fibrosis. The diagnostic gold-standard is still the liver biopsy, even though the development of newer non-invasive techniques, like serological and imaging (radiology), have opened a new field for research that allows bloodless testing of these patients and better study of the natural history of this disease. Nowadays, there is still no specific treatment for NAFLD. The development of healthy life habits and moderate exercise continue to be the pillars of treatment. Different pharmacological approaches have been studied and applied, such as the control of insulin resistance, lowering cholesterol levels, antioxidants, and other alternatives in experimental trials (AU)


Assuntos
Humanos , Masculino , Feminino , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/etiologia , Fígado Gorduroso/terapia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Prognóstico , História Natural/métodos , História Natural/tendências , Biomarcadores/análise , Biópsia/métodos , Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias Alcoólicas/fisiopatologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
12.
PLoS One ; 8(6): e66143, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23823085

RESUMO

AIMS: Accurate liver fibrosis staging is crucial for the management of chronic hepatitis C (CHC). The invasiveness and cost burden of liver biopsy have driven the search for new noninvasive biomarkers of fibrosis. Based on the link between serum angiopoietin-1 and 2 levels and CHC progression, we aimed to determine the value of these angiogenic factors as noninvasive biomarkers of liver fibrosis. METHODS: Serum levels of angiopoietin-1 and -2 were measured by ELISA in 108 CHC patients who underwent pretreatment liver biopsy. The correlation between angiopoietins and clinical and demographic variables with liver fibrosis was analyzed by univariate regression. Significant factors were then subjected to multivariate analysis, from which we constructed a novel noninvasive liver fibrosis index (AngioScore), whose performance was validated in an independent series of 71 CHC patients. The accuracy of this model was compared with other documented fibrosis algorithms by De Long test. RESULTS: Angiopoietins correlated significantly with hepatic fibrosis; however, only angiopoietin-2 was retained in the final model, which also included age, platelets, AST, INR, and GGT. The model was validated and behaved considerably better than other fibrosis indices in discriminating all, significant, moderate and severe liver fibrosis (0.886, 0.920, 0.923). Using clinically relevant cutoffs, we classified CHC patients by discarding significant fibrosis and diagnosing moderate and severe fibrosis with greater accuracy, sensitivity, and specificity. CONCLUSIONS: Our novel noninvasive liver fibrosis model, based on serum angiopoietin-2 levels, outperforms other indices and should help substantially in managing CHC and monitoring long-term follow-up prognosis.


Assuntos
Angiopoietina-2/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/patologia , Neovascularização Patológica , Adulto , Idoso , Angiopoietina-1/sangue , Biópsia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade
13.
Med. clín (Ed. impr.) ; 140(11): 508-513, jun. 2013. ilus
Artigo em Espanhol | IBECS | ID: ibc-112478

RESUMO

La infección por el virus de la hepatitis B genera frecuentemente una inflamación crónica del hígado, que evoluciona a cirrosis y hepatocarcinoma en un elevado porcentaje de pacientes. La activación persistente del sistema inmunitario origina un daño hepático continuado que estimula de forma desorganizada fenómenos de reparación y remodelado tisular. La proteína viral X (HBx) es imprescindible para la replicación del virus y, por tanto, para el mantenimiento crónico de la infección. El principal potencial oncogénico de HBx reside, por una parte, en su capacidad para integrarse al ADN celular, y por otra, en la transactivación de diversas vías de señalización implicadas en crecimiento celular, apoptosis y reparación del ADN. Además, HBx interacciona con el proteasoma y es capaz de modificar la homeostasis del calcio celular. Esta revisión analiza el papel de HBx en la progresión de la hepatitis crónica B a través de sus efectos en procesos angiogénicos, fibrogénicos y oncogénicos (AU)


The infection by hepatitis B virus often promotes chronic liver inflammation which progresses to cirrhosis and hepatocellular carcinoma in a high percentage of patients. The persistent activation of the immune system causes an incessant liver damage, which fosters a disorganized stimulation of tissue repair and remodelling phenomena. In turn, the viral protein X (HBx) is essential for virus replication and therefore for the maintenance of chronic infection. However, the important oncogenic potential of HBx seems to reside, on one hand, in its ability to integrate into cellular DNA and, additionally, in the transactivation of different cellular signaling pathways involved in cell growth regulation, apoptosis and DNA repair. HBx also interacts with proteasome subunits and notably affects mitochondrial electric potential, thus altering cellular calcium homeostasis. Finally, this review discusses the pathogenic role of HBx in the progression of chronic hepatitis B through its effects on angiogenic, fibrogenic and oncogenic processes (AU)


Assuntos
Humanos , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/fisiopatologia , Proteína X Associada a bcl-2/análise , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia
17.
Liver Int ; 33(6): 864-70, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23419030

RESUMO

BACKGROUND: Monocytes are essential precursors of antigen-presenting cells, such as macrophages and dendritic cells, and contribute to the pathogenesis of chronic inflammatory diseases and cancer. AIMS: As Tie2-expressing monocytes (TEMs) are increased in the peripheral blood of patients with chronic hepatitis C (CHC), we aimed to examine the expression of Tie2 and angiopoietins (Ang1 and Ang2) during monocyte differentiation and maturation in CHC. METHODS: The expression of Tie2, CD11b, CD80, CD83, CD86 and MHC-II was measured by flow cytometry in peripheral blood monocytes and monocytes-derived cells (Mo-DCs) from nine healthy subjects and eight CHC patients whose HCV infection was unresolved after combination therapy. Ang1 and Ang2 levels were measured in cellular supernatants by ELISA. RESULTS: Mo-DCs from CHC patients expressed differential patterns of maturation markers compared with controls--primarily with regard to CD80. Tie2 was downregulated during monocyte differentiation in controls and CHC patients, whereas Ang1 expression was constant. However, Ang2 levels fell significantly during the differentiation of control monocytes, in contrast with those from CHC patients in whom Ang2 expression remained stable throughout differentiation. CONCLUSIONS: Altered expression of the Ang/Tie2 system in monocytes and Mo-DCs from CHC patients might account for the inflammatory and angiogenic disorders that are related to CHC. An increased understanding of Ang/Tie2 system regulation might be helpful in designing strategies to prevent CHC progression.


Assuntos
Angiopoietina-2/metabolismo , Diferenciação Celular , Células Dendríticas/metabolismo , Hepatite C Crônica/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Angiopoietina-1/metabolismo , Antivirais/uso terapêutico , Biomarcadores/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/virologia , Receptor TIE-2/metabolismo
18.
J Crohns Colitis ; 7(2): e61-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22552273

RESUMO

Primary sclerosing cholangitis is a chronic progressive disorder which involves the medium size and large ducts in the intrahepatic and extrahepatic biliary tree. The great majority of cases have underlying inflammatory bowel disease, mainly ulcerative colitis. A higher risk of colorectal cancer has been described among ulcerative colitis patients with primary sclerosing cholangitis. Here we report a case of a primary sclerosing cholangitis in a young male with a newly diagnosed ulcerative colitis presenting with colonic dysplasia. Surveillance for colorectal cancer should be strongly recommended in this group of patients.


Assuntos
Colangite Esclerosante/complicações , Colite Ulcerativa/complicações , Colo/patologia , Neoplasias Colorretais/prevenção & controle , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Azatioprina/uso terapêutico , Colangite Esclerosante/tratamento farmacológico , Colectomia , Colite Ulcerativa/tratamento farmacológico , Colo/cirurgia , Humanos , Imunossupressores/uso terapêutico , Infliximab , Masculino
19.
Med Clin (Barc) ; 140(11): 508-13, 2013 Jun 04.
Artigo em Espanhol | MEDLINE | ID: mdl-23245531

RESUMO

The infection by hepatitis B virus often promotes chronic liver inflammation which progresses to cirrhosis and hepatocellular carcinoma in a high percentage of patients. The persistent activation of the immune system causes an incessant liver damage, which fosters a disorganized stimulation of tissue repair and remodelling phenomena. In turn, the viral protein X (HBx) is essential for virus replication and therefore for the maintenance of chronic infection. However, the important oncogenic potential of HBx seems to reside, on one hand, in its ability to integrate into cellular DNA and, additionally, in the transactivation of different cellular signaling pathways involved in cell growth regulation, apoptosis and DNA repair. HBx also interacts with proteasome subunits and notably affects mitochondrial electric potential, thus altering cellular calcium homeostasis. Finally, this review discusses the pathogenic role of HBx in the progression of chronic hepatitis B through its effects on angiogenic, fibrogenic and oncogenic processes.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Transativadores/fisiologia , Apoptose , Carcinoma Hepatocelular/virologia , Regulação Viral da Expressão Gênica , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/ultraestrutura , Hepatite B Crônica/imunologia , Hepatite B Crônica/fisiopatologia , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Evasão da Resposta Imune , Neoplasias Hepáticas/virologia , Potencial da Membrana Mitocondrial , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Transativadores/genética , Ativação Transcricional , Proteínas Virais Reguladoras e Acessórias , Integração Viral , Replicação Viral
20.
J Hepatol ; 58(3): 452-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23159770

RESUMO

BACKGROUND & AIMS: Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC(3) included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. METHODS: Patients with F2/F3 MFS who failed retreatment were randomized to PegIFNα-2b (0.5 µg/kg/week, n=270) or observation (n=270) for 36 months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest. RESULTS: In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PegIFNα-2b and 11% of observation patients had improvement in MFS (p=0.32). More PegIFNα-2b than observation patients had improvement in activity score (20% vs. 9%; p <0.001). Among patients treated for >2.5 years, improvement in MFS or activity score was more common with PegIFNα-2b than observation (21% vs. 14%, p=0.08 and 26% vs. 10%, p <0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PegIFNα-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PegIFNα-2b was similar to previous studies. CONCLUSIONS: PegIFNα-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5 years. Both FibroTest and ActiTest were significantly improved during maintenance therapy.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Inflamação/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Alanina Transaminase , Feminino , Hepatite C/patologia , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
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