RESUMO
UNLABELLED: Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). CONCLUSION: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC.
Assuntos
Carcinoma Hepatocelular/complicações , Complicações do Diabetes/complicações , Hepatite C Crônica/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Adulto , Antivirais/uso terapêutico , Índice de Massa Corporal , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Albumina Sérica/metabolismo , Índice de Gravidade de DoençaRESUMO
Non-invasive pulse spectrophotometry to measure indocyanine green (ICG) elimination correlates well with the conventional invasive ICG clearance test. Nevertheless, the precision of this method remains unclear for any application, including small-for-size liver remnants. We therefore measured ICG plasma disappearance rate (PDR) during the anhepatic phase of orthotopic liver transplantation using pulse spectrophotometry. Measurements were done in 24 patients. The median PDR after exclusion of two outliers and two patients with inconstant signal was 1.55%/min (95% confidence interval [CI]=0.8-2.2). No correlation with patient age, gender, body mass, blood loss, administration of fresh frozen plasma, norepinephrine dose, postoperative albumin (serum), or difference in pre and post transplant body weight was detected. In conclusion, we found an ICG-PDR different from zero in the anhepatic phase, an overestimation that may arise in particular from a redistribution into the interstitial space. If ICG pulse spectrophotometry is used to measure functional hepatic reserve, the verified average difference from zero (1.55%/min) determined in our study needs to be taken into account.
Assuntos
Corantes/farmacocinética , Verde de Indocianina/farmacocinética , Transplante de Fígado/fisiologia , Monitorização Intraoperatória/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Espectrofotometria/métodosRESUMO
BACKGROUND: Clinical outcomes of chronic hepatitis C infection in patients with advanced fibrosis include liver failure, hepatocellular carcinoma, and death. OBJECTIVE: To investigate whether sustained virologic response to treatment for hepatitis C is associated with improved clinical outcomes. DESIGN: Retrospective cohort study. SETTING: 5 hepatology units of tertiary care centers in Europe and Canada caring for patients with chronic hepatitis C treated between 1990 and 2003. PATIENTS: Consecutively treated patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6). MEASUREMENTS: Sustained virologic response, defined as absence of detectable hepatitis C virus RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver failure, and hepatocellular carcinoma. RESULTS: Of 479 patients, 29.6% had sustained virologic response and 70.3% did not. Median follow-up was 2.1 years (interquartile range, 0.8 to 4.9 years). Four patients with and 83 without sustained virologic response had at least 1 outcome event. Sustained virologic response was associated with a statistically significant reduction in the hazard of events (adjusted hazard ratio, 0.21 [95% CI, 0.07 to 0.58]; P = 0.003). The effect was largely attributable to a reduction in liver failure, which developed in no patients with and 42 patients without sustained virologic response (5-year occurrence, 0% vs. 13.3% [CI, 8.4% to 18.2%]; unadjusted hazard ratio, 0.03 [CI, 0.00 to 0.91]). LIMITATIONS: Because few events occurred in the sustained virologic response group, the study had limited ability to detect differences between groups in individual outcomes. In addition, the study was retrospective; selection and survival biases may therefore influence estimates of effect. CONCLUSION: Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Carcinoma Hepatocelular/etiologia , Quimioterapia Combinada , Feminino , Seguimentos , Hepatite C Crônica/complicações , Humanos , Interferon alfa-2 , Cirrose Hepática/etiologia , Falência Hepática/etiologia , Falência Hepática/mortalidade , Neoplasias Hepáticas/etiologia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Proteínas Recombinantes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Herbal agents are popular and perceived as safe because they are supposedly 'natural'. We report 10 cases of toxic hepatitis implicating Herbalife products. METHODS: To determine the prevalence and outcome of hepatotoxicity due to Herbalife products. A questionnaire was sent to all public Swiss hospitals. Reported cases were subjected to causality assessment using the CIOMS criteria. RESULTS: Twelve cases of toxic hepatitis implicating Herbalife preparations (1998-2004) were retrieved, 10 sufficiently documented to permit causality analysis. Median age of patients was 51 years (range 30-69) and latency to onset was 5 months (0.5-144). Liver biopsy (7/10) showed hepatic necrosis, marked lymphocytic/eosinophilic infiltration and cholestasis in five patients. One patient with fulminant liver failure was successfully transplanted; the explant showed giant cell hepatitis. Sinusoidal obstruction syndrome was observed in one case. Three patients without liver biopsy presented with hepatocellular (2) or mixed (1) liver injury. Causality assessment of adverse drug reaction was classified as certain in two, probable in seven and possible in one case(s), respectively. CONCLUSIONS: We present a case series of toxic hepatitis implicating Herbalife products. Liver toxicity may be severe. A more detailed declaration of components and pro-active role of regulatory agencies would be desirable.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Suplementos Nutricionais/efeitos adversos , Adulto , Idoso , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ephedra/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários , Suíça/epidemiologiaRESUMO
We analyzed databases spanning 50 years, which included retrospective alveolar echinococcosis (AE) case finding studies and databases of the 3 major centers for treatment of AE in Switzerland. A total of 494 cases were recorded. Annual incidence of AE per 100,000 population increased from 0.12-0.15 during 1956-1992 and a mean of 0.10 during 1993-2000 to a mean of 0.26 during 2001-2005. Because the clinical stage of the disease did not change between observation periods, this increase cannot be explained by improved diagnosis. Swiss hunting statistics suggested that the fox population increased 4-fold from 1980 through 1995 and has persisted at these higher levels. Because the period between infection and development of clinical disease is long, the increase in the fox population and high Echinococcus multilocularis prevalence rates in foxes in rural and urban areas may have resulted in an emerging epidemic of AE 10-15 years later.
Assuntos
Equinococose Hepática/epidemiologia , Raposas/parasitologia , Interações Hospedeiro-Parasita , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Equinococose Hepática/transmissão , Echinococcus multilocularis/patogenicidade , Humanos , Incidência , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , População Rural , Suíça/epidemiologia , População Urbana , ZoonosesRESUMO
BACKGROUND/AIMS: Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. METHODS: Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR. RESULTS: Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. CONCLUSIONS: Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.
Assuntos
Imunossupressores/administração & dosagem , Cirrose Hepática Experimental , Sirolimo/administração & dosagem , Administração Oral , Aminopirina , Animais , Western Blotting , Testes Respiratórios/métodos , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Expressão Gênica , Imunossupressores/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Cirrose Hepática Experimental/mortalidade , Cirrose Hepática Experimental/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirolimo/uso terapêutico , Taxa de Sobrevida/tendências , Fator de Crescimento Transformador beta1/biossíntese , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta2/biossíntese , Fator de Crescimento Transformador beta2/genética , Resultado do TratamentoRESUMO
Altered activity of retinal endothelin-1 (ET-1) and nitric oxide may play a causal role in the hemodynamic and histopathological changes of diabetic retinopathy. This study evaluated the therapeutic potential of long-term selective blockade of the ET-1(A) receptor (ETRA) to prevent the development of retinopathy in a genetic mouse model of nonobese type 1 diabetes (NOD). Mice with NOD that received subcutaneous implantation of insulin pellets and wild-type control mice were treated for 4 months with the selective ETRA antagonist LU208075 (30 mg/kg/day) via drinking water. At the end of the study, blood glucose levels were evaluated, and animals were anesthetized and perfused intracardially with FITC-labeled dextran. Retinas were removed and either fixed in formalin for confocal microscope evaluation of retinal vascular filling or transferred to RNALater for quantitative reverse transcriptase-polymerase chain reaction to evaluate expression of NOS-3, NOS-1, ET-1, ETRA, ETRB, and the angiogenic factor adrenomedullin. Compared with wild-type controls, expression of ET-1, ETRA, ETRB, and adrenomedullin in mice with NOD were markedly upregulated in the retinas of nontreated mice (cycle time values relative to GAPDH [deltaCt], 14.8 vs. 13.7, 18.57 vs. 17.5, 10.76 vs. 9.9, and 11.7 vs. 9.1, respectively). Mean integral fluorescence intensity (MIFI) of retinal vascular filling was reduced from normal values of 24 to 12.5 in nontreated animals. LU208075 treatment normalized the upregulated expression of ET-1 and adrenomedullin, as well as the deficit in MIFI, but did not affect the increased ETRA and ETRB expression or the elevated plasma glucose levels found in nontreated animals. NOS isoform expression was essentially unchanged. ETRA antagonists may provide a novel therapeutic strategy to slow or prevent progression of retinal microvascular damage and proliferation in patients for whom there is clear evidence of activation of the ET-1 system.
Assuntos
Retinopatia Diabética/prevenção & controle , Antagonistas do Receptor de Endotelina A , Endotelina-1/antagonistas & inibidores , Peptídeos/farmacologia , Vasodilatadores/farmacologia , Adrenomedulina , Animais , Glicemia/análise , Feminino , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Fenilpropionatos/farmacologia , Piridazinas , Fatores de TempoRESUMO
BACKGROUND/AIMS: Transactivated hepatic stellate cells (HSCs) represent the key source of extra cellular matrix (ECM) in fibrotic liver. Imatinib, a potent inhibitor of the PDGF receptor tyrosine kinase, reduces HSC proliferation and fibrogenesis when treatment is initiated before fibrosis has developed. We tested the antifibrotic potential of imatinib in ongoing liver injury and in established fibrosis. METHODS: BDL-rats were gavage fed with 20 mg/kg/d imatinib either early (days 0-21) or late (days 22-35) after BDL. Untreated BDL-rats served as controls. ECM and activated HSCs were quantified by morphometry. Tissue activity of MMP-2 was determined by gelatin zymography. mRNA expression of TIMP-1 and procollagen alpha1(I) were measured by RT-PCR. Liver tissue concentration of imatinib was measured by tandem mass spectrometry. RESULTS: Early imatinib reduced ECM formation by 30% (P=0.0455) but left numbers of activated HSCs and procollagen I expression unchanged. MMP-2 activity and TIMP-1 expression were reduced by 50%. Late imatinib treatment did not alter histological or molecular markers of fibrogenesis despite high imatinib tissue levels. CONCLUSIONS: The antifibrotic effectiveness of imatinib is limited to the early phase of fibrogenesis. In ongoing liver injury other mediators most likely compensate for the inhibited PDGF effect.
Assuntos
Cirrose Hepática Experimental/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Administração Oral , Animais , Benzamidas , Biomarcadores/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Progressão da Doença , Seguimentos , Mesilato de Imatinib , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Espectrometria de Massas , Metaloproteinase 2 da Matriz/metabolismo , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Pró-Colágeno/genética , Pró-Colágeno/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Chronic portal hypertension is accompanied by a nitric oxide (NO) dependent vasodilation. Three isoforms of NO producing synthases (NOS) are characterized: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Sources of increased NO levels in chronic hypertension is disputed. METHODS: To determine eNOS and iNOS expression in different organs of portal hypertensive and control rats, we divided Sprague-Dawley rats in 6 groups: (1). Partial portal vein ligated rats, (2). Bile duct ligated rats, (3). Carbon tetrachloride treated rats, (4). Sham operated rats, (5). Untreated control rats, and (6). LPS treated rats. Immunohistochemistry (IHC) and immunoblotting (IB) using antibodies against eNOS or iNOS were carried out on samples from thymus, aorta, heart, lung, oesophagus, liver, spleen, kidney, pancreas, small and large intestine. RESULTS: IHC revealed an even eNOS expression in all groups. Expression of iNOS was restricted to macrophages in organs of LPS treated and the thymus of rats. IB mirrored these results. CONCLUSION: In chronic portal hypertension, the main source for NO production depends on eNOS activity.