RESUMO
BACKGROUND: A sustained virological response (SVR) is the major end point of therapy for chronic hepatitis C virus (HCV) infection. Late relapse of infection is rare and poorly characterized. Three of 103 patients with a SVR treated at the National Institutes of Health had late relapse. We evaluated HCV RNA sequences in serum and liver tissue to distinguish relapse from reinfection. METHODS: Per patient, 10-22 clones of amplified 5' untranslated region were evaluated in pretreatment and relapse serum specimens and in liver biopsy specimens obtained during SVR. Genotypes and sequence diversity were evaluated. Four patients whose infection relapsed before they reached a SVR (ie, the early relapse group) were used as a comparison. RESULTS: Results of tests for detection of serum HCV RNA in all patients with late relapse were repeatedly negative during the first 24 weeks after therapy but became positive 8, 75, and 78 months after SVR. Reinfection risk factors were absent in 2 of 3 patients. In all patients with early or late relapse, apart from minor variations, the original HCV sequence was present before treatment and after relapse. All liver biopsy specimens from patients with late relapse were HCV RNA positive at SVR, with sequences nearly identical to those of specimens obtained at other time points. CONCLUSIONS: Sequence comparisons suggest that reappearance of HCV RNA years after a SVR can be from relapse of the initial viral infection rather than reinfection from a different virus.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Adulto , Feminino , Genótipo , Humanos , Fígado/química , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Viral/análise , RNA Viral/genética , Recidiva , Alinhamento de SequênciaRESUMO
Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10-39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE. Twenty-three patients were evaluated (mean age = 34.3 years, standard deviation = 7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P = 0.01) and TRV (P = 0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P < 0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (P = 0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P = 0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (P = 0.0037) and TRV (P = 0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P = 0.041), lower albumin (P = 0.046), hemoglobin/hematocrit (P < 0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC.
Assuntos
Anemia Falciforme/fisiopatologia , Arteriopatias Oclusivas/etiologia , Insuficiência Hepática/etiologia , Fígado/química , Insuficiência Venosa/etiologia , Adulto , Anemia Falciforme/imunologia , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Biomarcadores , Estudos de Coortes , Estudos Transversais , Diagnóstico Precoce , Elasticidade , Técnicas de Imagem por Elasticidade , Feminino , Hemólise , Insuficiência Hepática/diagnóstico , Insuficiência Hepática/fisiopatologia , Humanos , Tempo de Internação , Fígado/imunologia , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/etiologia , Masculino , Índice de Gravidade de Doença , Insuficiência da Valva Tricúspide/etiologiaRESUMO
BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is characterized by lack of immune-mediated liver injury despite a high level of HCV replication during the incubation phase, which lasts about 8 weeks. We investigated whether this results from delayed recruitment of HCV-specific T cells and whether it facilitates HCV persistence. METHODS: Six chimpanzees were infected with HCV; blood and liver samples were collected for 28 weeks and analyzed for immune cells and chemokines. RESULTS: Two chimpanzees developed self-limited infections, whereas the remaining 4 developed chronic infections. Levels of the chemokines CXCL10, CXCL11, CCL4, and CCL5 increased in blood and liver samples from all chimpanzees within 1 month of HCV infection. Chemokine induction correlated with intrahepatic type I interferon (IFN) responses in vivo and was blocked by neutralizing antibodies against IFN-ß in vitro. Despite the early-stage induction of chemokines, the intrahepatic lymphocytic infiltrate started to increase no earlier than 8 weeks after HCV infection, when HCV-specific, tetramer-positive CD8(+) T cells appeared in the circulation. The HCV-specific CD8(+) T cells expressed chemokine receptors when they were initially detected in blood samples, so they could be recruited to the liver as soon as they entered the circulation. CONCLUSIONS: Chemokines are induced during early stages of HCV infection, which requires a type I IFN-mediated response. The delayed onset of acute hepatitis does not result from delayed recruitment of HCV-specific T cells, but could instead be related to a primary delay in the induction of HCV-specific T cells. Divergent outcomes occur without evident differences in chemokine induction and T-cell recruitment.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/imunologia , Quimiocinas/imunologia , Hepatite C/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , RNA Mensageiro/metabolismo , RNA Viral/imunologia , Alanina Transaminase/sangue , Animais , Anticorpos/imunologia , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Carcinoma Hepatocelular/metabolismo , Quimiocinas/sangue , Hepatite C/sangue , Molécula 1 de Adesão Intercelular/metabolismo , Interferon beta/imunologia , Interferon beta/metabolismo , Interferon gama/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Modelos Animais , Pan troglodytes , RNA Viral/sangue , Fatores de Tempo , Células Tumorais Cultivadas , Molécula 1 de Adesão de Célula Vascular/metabolismo , Carga ViralRESUMO
BACKGROUND & AIMS: Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. METHODS: In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. RESULTS: Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). CONCLUSIONS: LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.