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UNLABELLED: Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. CONCLUSION: Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs.
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Antivirais/administração & dosagem , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Guanina/administração & dosagem , Humanos , Interferon alfa-2 , Masculino , Proteínas Recombinantes/administração & dosagemRESUMO
UNLABELLED: The present review includes translational and clinical research that characterize non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Clinical and experimental evidence led to the recognition of the key toxic role played by lipotoxicity in the pathogenesis of NAFLD. The current understanding of lipotoxicity suggests that organ injury is initiated by the generation of oxidative metabolites and the translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. The injury progresses through impairment of tissue regeneration and extracellular matrix turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, predominantly stellate cells, macrophages and parenchymal cells. In response to inflammation, cytokines activate many signaling cascades that regulate fibrogenesis. This examination brings together research focusing on the underlying mechanisms of injury. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, and fibrogenesis in the liver. We searched electronic databases (Medline, Embase) for this review. This integrative work investigates different aspects of liver damage and possible repair. We aim to (1) determine the immuno-pathology of liver damage due to steatosis, (2) suggest diagnostic markers of NASH, (3) examine the role of behaviour in the development of NASH, and (4) develop common tools to study steatosis-induced effects in clinical studies. Special accent is put on co-morbidities with renal and neuropsychological disorders. Moreover, we review the evidence in literature on the role of moderate alcohol consumption in individuals that present NAFLD/NASH. KEY WORDS: behavior, diet, imaging, non-alcoholic fatty liver, nonalcoholic steatohepatitis, laboratory markers.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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Hepatopatia Gordurosa não Alcoólica/metabolismo , Pesquisa Translacional Biomédica , Protocolos Clínicos , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
BACKGROUND & AIMS: ASP9831 is a phosphodiesterase-4 inhibitor developed to treat nonalcoholic steatohepatitis (NASH); it showed potent anti-inflammatory and antifibrotic effects in preclinical studies. We evaluated the efficacy and safety of ASP9831 in patients with NASH. METHODS: In a phase 1 trial, we determined the optimal therapeutic window of ASP9831 in healthy volunteers and evaluated 2 doses (50 and 100 mg) in patients with NASH. Based on the positive outcomes of the phase 1 study, we performed a phase 2 trial to compare the biochemical effects of ASP9831 vs placebo. Patients with NASH were assigned randomly to groups given either 50 mg (n = 33) or 100 mg (n = 33) ASP9831 twice daily, or placebo (n = 30), for 12 weeks. The primary end point was the mean percentage change, from baseline to the end of ASP9831 administration, in serum level of alanine aminotransferase (ALT); secondary outcomes included changes in aspartate aminotransferase (AST) levels, ratio of AST:ALT, and various biomarkers of NASH. RESULTS: After 12 weeks of administration, there was no significant change in mean serum levels of ALT (P = .42) or AST (P = .20) or other biomarkers in any group, and no significant differences were observed among groups. Most adverse events were mild; gastrointestinal disorders occurred more frequently in the ASP9831 groups than the placebo group. CONCLUSIONS: Despite a relevant mechanism of action, ASP9831 did not significantly alter the biochemical markers of NASH, compared with placebo, in a clinical trial. This highlights the difficulties of developing therapeutics for NASH and the need for more extensive preclinical testing of mechanisms of potential drug candidates. Clinicaltrialsregister.eu: 2005-001687-31; EudraCT numbers: 2007-002114-19.
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Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Placebos/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
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Fígado Gorduroso , Hepatopatia Gordurosa não Alcoólica , Animais , HumanosRESUMO
UNLABELLED: The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (> or =F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. CONCLUSION: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers.
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Algoritmos , Hepatite C Crônica/complicações , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Biópsia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Estudos RetrospectivosRESUMO
Arterial hypertension (HT) plays an important role and is a major factor in the occurrence and progression of chronic graft nephropathy. We evaluated 24-hour blood pressure (BP) profile in kidney transplant patients to identify factors predictive of abnormal circadian BP profile. BP was measured over a period of 24 hours using a noninvasive automatic device (EC-3H / ABPM) in 40 renal transplant patients (mean age = 37.2±12.2 years, M = 30, mean serum creatinine = 2.0±1.4 mg/dl). They were under the triple immunosuppressive therapy (CsA / Ts + Aza / MMF + PDN). 35 recipients (87.5%) had a nondipper BP profile, with nocturnal values which fell by less than 10% from the daytime BP values. The other 5 containers (12.5%) had normal dipper BP, with lower nighttime values by more than 10% of the daytime BP values. 17/40 recipients (42.5%) had nocturnal BP values higher than daily rates (extreme non-dipper). In none of the patients there has been excessive dipper profile (low nighttime values over 20% less than the diurnal BP). There were no statistically significant differences between the dipper and non-dipper recipients profile in terms of age, gender, creatinine, mean systolic BP (SBP) and daytime SBP, short-term variability in BP and pulse pressure (p>0.05). Factors predictive of a non-dipper BP profile were elevated median 24h BP, median 24 systolic and diastolic blood pressure (DBP), diurnal, nocturnal and 24h pulse rate (p<0.05). In conclusion, the absence of normal nocturnal BP lower values was relatively frequent (87.5%) in renal allograft recipients. In many studied patients nocturnal BP values were higher than the diurnal ones.
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AIM: To determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients. METHODS: One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems). RESULTS: Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%. CONCLUSION: HCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.
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Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/uso terapêutico , Mutação , Polietilenoglicóis/uso terapêutico , Proteínas do Core Viral/genética , Adolescente , Adulto , Idoso , Alelos , Feminino , Genótipo , Hepacivirus , Humanos , Interferons , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , População Branca , Adulto JovemRESUMO
Until the 1980s the role of bile acids in the initiation of liver injury in man was only suspected on the basis of the toxicity of whole bile and bile salts, and of studies showing elevations in serum and tissue levels of bile salts in liver diseases. The beneficial effects of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis have provided the first firm evidence that bile acids may in some way be related to injury in man. There are many questions regarding the hepato-protective effect of UDCA that should be addressed in the near future. In particular, we do not know how chronic cholestasis induces liver fibrosis and if UDCA can prevent or counteract this process. Most cholestatic diseases have an immune pathophysiological basis. We must learn much more about the impact of cholestasis and bile acids on the immune system, particularly on endogenous or exogenous peptide presentation in cells exposed to high concentrations of bile components. We have seen that the trafficking of transporters in hepatocytes may be affected by bile acids; efforts must be made to learn more about this important issue. Finally, structural analogues of UDCA or combinations of drugs should be studied, in order to determine if better therapeutic efficacy could be obtained.
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Colagogos e Coleréticos/uso terapêutico , Colestase/prevenção & controle , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Ácidos e Sais Biliares/metabolismo , Colagogos e Coleréticos/farmacocinética , Colagogos e Coleréticos/farmacologia , Colangite Esclerosante/fisiopatologia , Colestase/complicações , Colestase/fisiopatologia , Feminino , Hepatócitos/fisiologia , Humanos , Cirrose Hepática/prevenção & controle , Mitocôndrias Hepáticas/patologia , Estresse Oxidativo , Gravidez , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/prevenção & controle , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacologiaRESUMO
Hepatitis B virus (HBV) infection is a major health problem with an important biological and a significant socio-economic impact all over the world. There is a high pressure to come up with a new and more efficient strategy against HBV infection, especially after the recent success of HCV treatment. Preventing HBV infection through vaccine is currently the most efficient way to decrease HBV-related cirrhosis and liver cancer incidence, as well as the best way to suppress the HBV reservoir. The vaccine is safe and efficient in 80-95% of cases. One of its most important roles is to reduce materno-fetal transmission, by giving the first dose of vaccine in the first 24 hours after birth. Transmission of HBV infection early in life is still frequent, especially in countries with high endemicity. Successful HBV clearance by the host is immune-mediated, with a complex combined innate and adaptive cellular and humoral immune response. Different factors, such as the quantity and the sequence of HBV epitope during processing by dendritic cells and presenting by different HLA molecules or the polymorphism of T cell receptors (TOL) are part of a complex network which influences the final response. A new potential therapeutic strategy is to restore T-cell antiviral function and to improve innate and adaptive immune response by immunotherapeutic manipulation. It appears that HBV eradication is far from being completed in the next decades, and a new strategy against HBV infection must be considered.
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Antivirais/uso terapêutico , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B/patogenicidade , Hepatite B/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Imunidade Adaptativa , Animais , Antivirais/efeitos adversos , Feminino , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite B/transmissão , Vacinas contra Hepatite B/efeitos adversos , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Recém-Nascido , Masculino , Gravidez , Resultado do TratamentoRESUMO
UNLABELLED: The association of NAFLD with chronic hepatitis C (CHC) has been extensively studied but little is known about its coexistence with chronic hepatitis B (CHB). AIMS: To investigate the prevalence and determinants of steatosis and insulin resistance (IR) in CHB and its consequences on liver injury compared with CHC and NAFLD. METHODS: Patients with CHB (N=110), CHC (N=111) and NAFLD (N=136) were evaluated by biomarkers of steatosis (SteatoTest>0.38 as a surrogate for steatosis >5%), IR (HOMA-IR>2.7 as a surrogate for IR) and fibrosis (FibroTest>0.48 as a surrogate for significant fibrosis, ≥F2). RESULTS: HOMA-IR gradually increased in CHB, CHC and NAFLD: 2.3±1.8; 3±2.6 and 3.8±2.7 (p<0.001). The prevalence of steatosis >5% was 21% (CHB), 43% (CHC) and 82% (NAFLD), (p<0.001). The prevalence of fibrosis≥F2 was 10% (CHB), 42% (CHC) and 21% (NAFLD), p<0.001. In CHB, IR was related to host and not viral factors. CHB patients with steatosis had higher BMI (29±5.7kg/m(2) vs. 24±4kg/m(2), p<0.001), waist circumference (96±14cm vs. 84±11cm, p=0.001) and HOMA-IR (3.9±2.6 vs. 1.8±1.2, p<0.001) than those without steatosis. HOMA-IR independently predicted steatosis in CHB (OR=1.9, 95% CI, 1.09-3.27, p<0.05) and CHC (OR=1.38; 95% CI, 1.07-1.78, p<0.02). In CHB, metabolic risk factors and HOMA-IR were not associated with significant fibrosis. HOMA-IR was an independent predictor of fibrosis in CHC. CONCLUSIONS: Steatosis may co-exist in CHB patients but with a lower prevalence than in CHC and NAFLD. In CHB steatosis is related to host and not viral factors, and is not associated with the severity of fibrosis.
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Hepatite B Crônica/epidemiologia , Hepatite C Crônica/epidemiologia , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/epidemiologia , Adulto , Idoso , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Índice de Massa Corporal , Comorbidade , Feminino , Hepatite B Crônica/metabolismo , Hepatite C Crônica/metabolismo , Humanos , Cirrose Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Prevalência , Estudos Prospectivos , Índice de Gravidade de Doença , Triglicerídeos/metabolismo , Carga Viral , Circunferência da Cintura , gama-Glutamiltransferase/metabolismoRESUMO
Liver transplant currently represents the therapeutic method for irreversible acute and chronic liver diseases without any other available therapy. In some cases, before or after liver transplantation, it is necessary to replace the functions of the liver. We report the case of a 7 year-old female patient with type I glycogenosis who was transplanted in July 2001 using living-related donor transplantation and who developed chronic rejection two months later. In this case, we used MARS (Molecular Adsorbents Recirculating System) detoxification therapy to optimise the patient's clinical and biological status and to create a bridge that allowed the patient's survival until retransplantation was available. The therapy was well tolerated, with no major incidents. We noted favourable clinical effects and significant improvement in serum bilirubin level, urea nitrogen level and serum creatinine level. We consider that MARS treatment is a temporary solution for patients with acute and acute-on-chronic liver failure, indicated in those cases with real chances of recovery of the hepatic functions or in patients on the liver transplantation waiting list.
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Rejeição de Enxerto , Falência Hepática/cirurgia , Transplante de Fígado/efeitos adversos , Desintoxicação por Sorção/métodos , Criança , Feminino , Humanos , Reoperação , Resultado do Tratamento , Listas de EsperaRESUMO
Renal transplantation is often associated with severe complications. Except for acute rejection, infections and toxicity of immunosuppressive treatment are the most frequent problems observed after transplantation. Infections with hepatic viruses (HBV, HDV, HCV, HGV) and cytomegalic virus (CMV) are the main infectious complications after renal transplantation. Cyclosporine toxicity is not unusual for a patient with renal transplantation and is even more frequent for patients with hepatic impairment due to viral infections. The subjects of this report are two renal transplant recipients with acute pancreatitis, severe hepatitis and acute renal failure on graft, receiving immunosuppressive therapy for maintaining renal graft function
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Injúria Renal Aguda/etiologia , Hepatite/etiologia , Transplante de Rim , Pancreatite/etiologia , Complicações Pós-Operatórias , Doença Aguda , Injúria Renal Aguda/patologia , Injúria Renal Aguda/terapia , Adulto , Ciclosporina/efeitos adversos , Hepatite/patologia , Hepatite/terapia , Humanos , Imunossupressores/efeitos adversos , Masculino , Pancreatite/patologia , Pancreatite/terapia , Complicações Pós-Operatórias/terapiaRESUMO
Liver impairment in renal transplant recipients is not a common complication and is associated, in most cases, with viral infections (HBV, HCV, HVD, HGV) or drug hepatotoxicity (Cyclosporin, Azathioprine, statins). Cytomegalovirus (CMV) infection is common, with 50 to 80% of the adult population being seropositive for CMV antibodies. In immunocompetent individuals, primary infection is usually asymptomatic or associated with minor illness. CMV remains latent after primary infection. In immunocompromised patients, as in renal transplant recipients or transplant recipients of other solid organ or bone marrow, the virus can cause serious disease. This could be the result of newly acquired infection or reactivation of the latent virus. One of the organs involved in CMV disease is the liver. The subjects of this report are renal transplant recipients with liver impairment due to CMV induced acute hepatitis.
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Infecções por Citomegalovirus/diagnóstico , Hepatite Viral Humana/diagnóstico , Transplante de Rim , Adolescente , Adulto , Feminino , Hepatite Viral Humana/virologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-IdadeRESUMO
Non-alcoholic fatty liver disease (NAFLD) is by far the most common form of chronic liver disease worldwide, affecting adults as well as children. Under the term of NAFLD there is a wide spectrum of diseases ranging from simple steatosis to the non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC). Several mechanisms have been described to influence the progression of the disease from the benign NAFL to the aggressive NASH. The imbalance between pro- and anti-oxidant mechanisms and between pro- and anti-inflammatory cytokines is thought to play a pivotal role in the pathogenesis of NAFLD and disease progression toward NASH and fibrosis. The present review intends to look at some of the mechanistic biomarkers to be employed in establishing an early diagnosis in HCC derived from NASH.
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Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Animais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Incidência , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metabolômica , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND AND AIM: Development of contrast specific ultrasound techniques and introduction of the second-generation ultrasound contrast agents have improved the ability of this technique in detecting and characterizing focal liver lesions (FLLs). The purpose of this study was to present the experience of four Romanian centers in the evaluation of FLLs by contrast enhanced ultrasound (CEUS), in daily practice. MATERIALS AND METHODS: We performed a multicentre retrospective study, including 1244 FLLs, evaluated by means of CEUS in four Romanian centers with extensive experience in ultrasound, during September 2009-December 2010. RESULTS: This study included 1244 FLLs, both "de novo" (1056 cases) and pre-existing (such as hepatocellular carcinomas evaluated after percutaneous treatment to assess the treatment results). In 1046/1244 of cases (84.1%), CEUS showed a typical pattern of enhancement (according to the EFSUMB Guidelines 2008), thus being sufficient for a correct and final diagnosis, while in 198/1244 of cases (15.9%), other methods of diagnosis were required, such as contrast CT/MRI or biopsy. In our study, CEUS established the benign or malignant nature of lesions in 1139/1244 of cases (91.5%). CONCLUSION: According to our results, CEUS could be the first imaging method of diagnosis for uncharacteristic FLLs detected by standard ultrasound, providing a correct classification in 84.1% of cases and a correct differentiation between benign/malignant lesions in 91.5% of cases. Thus, when faced with an uncharacteristic FLL on standard ultrasound, our local strategy is to perform CEUS as a first-line imaging investigation.
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Meios de Contraste/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/epidemiologia , Padrões de Prática Médica/estatística & dados numéricos , Ultrassonografia/estatística & dados numéricos , Feminino , Humanos , Neoplasias Hepáticas/terapia , Masculino , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Romênia/epidemiologia , Sensibilidade e Especificidade , Resultado do Tratamento , Revisão da Utilização de Recursos de SaúdeRESUMO
OBJECTIVES: Scientific literature indicates that the risk of coronary heart disease morbidity and death among peritoneal dialysis patients exceeds risk observed in non-renal patients. The aims of this study were to establish the independent predictors associated with increased risk of coronary heart disease in peritoneal dialysis patients without diabetic nephropathy. MATERIALS AND METHODS: A number of 116 end-stage renal disease patients without diabetic nephropathy undergoing peritoneal dialysis were evaluated for coronary heart disease and predictive risk factors were investigated and identified. Also intima-media thickness measurements, as an early sign of atherosclerosis, were analyzed in a subset of patients in correlation with a number of traditional and non-traditional cardiovascular risk factors. RESULTS: The study sample was found to be characterized by a high prevalence of traditional risk factors: hypertension (95.7%), dyslipidemia (93.1%) and metabolic syndrome (58.6%), but also of dialysis-related risk factors: inflammation (82.8%) and anemia (55.2%). Independent variables found to be associated in regression analysis with coronary heart disease were: age, smoking status, nephroangiosclerosis, albumin, C-reactive protein and iPTH levels. Intima-media thickness was significantly higher in patients with coronary heart disease, values greater than 0.89 mm being associated with increased risks for coronary heart disease, acute coronary syndrome and cardiovascular death. CONCLUSIONS: The prevalence of traditional cardiovascular risk factors in these peritoneal dialysis patients is extremely high, but there are also some other factors involved, especially malnutrition and inflammation. Age higher than 55 years, smoking, albumin less than 3.5 g/dl, iPTH less than 150 pg/ml and nephroangiosclerosis were associated with highest odds ratio for coronary heart disease. An increasing CRP levels was associated with an increasing gradient for coronary heart disease risk.
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INTRODUCTION: Chronic HCV infection represents a public health problem in Romania, with a prevalence of 3.23-4.56%, and more than 5,000 patients on the waiting lists for antiviral therapy. AIM: To perform an evaluation of the severity of chronic HCV infection genotype 1b, and a quantification of patients with a low viral load, in order to quantify the number of patients who may be considered for shortened treatment duration. MATERIAL: Histological assessment and viral load were performed in 1,220 consecutive patients from the waiting list for antiviral therapy in 2009. The severity of chronic hepatitis was assessed by histological evaluation (the necrotic-inflammatory index - Metavir and the fibrosis score - Metavir). Viral load was measured by PCR and 400,000 UI/ml and 600,000 UI/ml were defined as thresholds for low versus high viral load We assessed the influence of age, sex, and viral load on necro-inflammatory activity and fibrosis. RESULTS: The mean age of the patients included was 48 ± 10.69 years and females predominated (58%). Many of them (60%) were in stage F3, with a high potential for disease progression in the next 10 years (necro-inflammatory activity was moderate to severe in over 90%). Almost half of the patients had low viral load, below 600,000 copies/ml. The viral load was significantly associated with the age (p< 0.001) and sex (p< 0.001) of the patients. CONCLUSION: Chronic HCV hepatitis in patients on the waiting lists for antiviral therapy in Romania has a high severity with important predictable consequences on the duration of life, complications and treatment costs. The strategy of shortening the duration of treatment would be beneficial for almost 50% of the patients.
Assuntos
Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Genótipo , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Romênia , Carga Viral , Listas de EsperaRESUMO
AIM: To evaluate the prevalence of HBV, HCV, HDV and HEV infections in populations with different categories of risk and the seroprevalence of HBV and HCV infections in subjects asking for a medical examination. METHOD: We conducted a cross-sectional, epidemiological study in 2,851 subjects from the SubCarpathian and South-Eastern Romania (including 17 counties, 34% of the country area and 42% of the population). The subjects were divided into four groups: controls (n=2,540, i.e. consecutive subjects asking for a medical examination), subjects with very low risk (students; n=44), with low risk (doctors and nurses; n=93) and with high risk for viral hepatitis (hemodialysis patients; n=174). All subjects were screened for HBsAg, antiHCV and ALT level. In populations at risk, antiHBs, HBeAg, antiHBe, antiHBc (IgG), HBV-DNA, HCV-RNA, antiHDV(IgG) and antiHEV(IgG) were also assessed. RESULTS: In controls, HBV seroprevalence was 5.59% and HCV seroprevalence 4.56%. The risk factors for HBV infection were: age, male gender and South-East region of Romania. The risk factors for HCV infection were: age, female gender, elevated ALT level and the South-East region of Romania. In the very low risk population HBV, HCV, HDV and HEV seroprevalence was: 2.27%, 0%, 0% and 12.5%, respectively. In low risk population the seroprevalence was 2.15%, 1.07%, 0% and 13.98%. In hemodialysis patients, HBV and HCV seroprevalence were 7.91%, respectively 39.26%. HCV-RNA was detectable in 20.69% cases. CONCLUSION: In the South and South-Eastern Romania the seroprevalence of viral hepatitis infections is intermediate, similar to other Romanian regions or the Balkans.