RESUMO
Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.
Assuntos
Doenças Biliares/tratamento farmacológico , Sistema Biliar/efeitos dos fármacos , Curcumina/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Animais , Sistema Biliar/metabolismo , Sistema Biliar/patologia , Doenças Biliares/metabolismo , Doenças Biliares/patologia , Curcuma , Curcumina/efeitos adversos , Curcumina/isolamento & purificação , Humanos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Fitoterapia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/isolamento & purificação , Plantas MedicinaisRESUMO
UNLABELLED: Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. MATERIAL AND METHODS: This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. RESULTS: Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. CONCLUSIONS: Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.
Assuntos
Fosfatase Alcalina/sangue , Colangite Esclerosante/sangue , Transplante de Fígado , Adulto , Neoplasias dos Ductos Biliares/epidemiologia , Bilirrubina/sangue , Biomarcadores/sangue , Colagogos e Coleréticos/uso terapêutico , Colangiocarcinoma/epidemiologia , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/mortalidade , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Tempo , Ácido Ursodesoxicólico/uso terapêuticoAssuntos
Colangite Esclerosante/complicações , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer/métodos , Doenças Inflamatórias Intestinais/complicações , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/terapia , Colectomia , Pólipos do Colo/etiologia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/cirurgia , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/terapia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Valor Preditivo dos Testes , Fatores de Risco , Fatores de TempoRESUMO
INTRODUCTION: Anastomotic biliary strictures (ABS) are a significant clinical problem associated with decreased survival post-liver transplantation (LT). Contributing to the morbidity of ABS is the need for early (i.e. emergent or unplanned) repeat endoscopic retrograde cholangiopancreatographies (ER-ERCPs). Our aim was to determine clinical, operative, and endoscopic predictors of ER-ERCP in patients with ABS. MATERIAL AND METHODS: Medical records of 559 patients who underwent LT at our institution from 2000-2012 were retrospectively reviewed for pertinent data. The primary endpoint was need for ER-ERCP. Seventeen potential predictors of ER-ERCP were assessed in bivariate analyses, and those with p < 0.20 were included in multivariate regression models. RESULTS: Fifty-four LT patients developed ABS and underwent a total of 200 ERCPs, of which 40 met criteria for ER-ERCP. Predictors of ER-ERCP in bivariate analyses included balloon dilation within 3 months post-LT and donation after cardiac death (both p < 0.05). Balloon dilation within 3 months post-LT was also associated with shorter ER-ERCP-free survival (p = 0.02). Moreover, a significantly higher proportion (67%) of patients who underwent balloon dilation within 3 months post-LT subsequent experienced ≥ 1 ER-ERCP (p = 0.03), and those who experienced ≥ 1 ER-ERCP had lower stricture resolution rates at the end of endoscopic therapy compared to those who did not (79 vs. 97%, p = 0.02). In multivariate analyses, balloon dilation within 3 months post-LT was the strongest predictor of ER-ERCP (OR 3.8, 95% CI 1.7-8.6, p = 0.001). CONCLUSIONS: Balloon dilation of ABS within 3 months post-LT is associated with an increased risk of ER-ERCP, which itself is associated with lower ABS resolution rates. Prospective studies are needed to confirm these findings and their implications for endoscopic management and follow-up of post-LT ABS.
Assuntos
Ductos Biliares/cirurgia , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colestase/cirurgia , Transplante de Fígado/efeitos adversos , Implantação de Prótese/métodos , Stents , Adulto , Idoso , Anastomose Cirúrgica/efeitos adversos , Colestase/epidemiologia , Colestase/etiologia , Constrição Patológica , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reoperação , Fatores de Risco , Estados UnidosRESUMO
INTRODUCTION: Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. MATERIAL AND METHODS: Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models. RESULTS: The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). CONCLUSIONS: Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.
Assuntos
Neoplasias dos Ductos Biliares/imunologia , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/imunologia , Colangite Esclerosante/imunologia , Imunoglobulina E/sangue , Transplante de Fígado , Adulto , Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/etiologia , Colangite Esclerosante/complicações , Colangite Esclerosante/mortalidade , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Doença Hepática Terminal , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
INTRODUCTION: Sirolimus has inhibitory effects on epithelial healing and cholangiocyte regeneration. In liver transplantation (LT) patients, these effects may be greatest at the biliary anastomosis. We therefore investigated whether sirolimus use is associated with need for early or emergent repeat therapeutic endoscopic retrograde cholangiography (ERC) in LT patients with anastomotic biliary stricture (ABS). MATERIAL AND METHODS: Medical records of patients who underwent LT from 1998-2009 at Johns Hopkins were reviewed and patients with ABS identified. Primary outcome was early repeat ERC, defined as need for unscheduled (i.e. unplanned) or emergent repeat therapeutic ERC. Univariate and multivariate logistic regression analyses (adjusting for age, sex, LT to ERC time, and stent number) were performed to assess association between sirolimus and early repeat ERC. RESULTS: 45 patients developed ABS and underwent 156 ERCs total. Early (median 26 days) repeat ERC occurred in 14/56 (25%) and 6/100 (6%) ERCs performed with and without concomitant sirolimus-based immunosuppression, respectively (OR 1.22; 95% CI 1.02-1.45; p = 0.03). In multivariate analysis, sirolimus use was associated with early repeat ERC (OR 1.24; 95% CI 1.04-1.47; p = 0.015); this association remained significant when sirolimus dose was modeled as a continuous variable (OR 1.04 for each mg of sirolimus per day; 95% CI 1.02-1.08; p = 0.038). CONCLUSIONS: Sirolimus-based immunosuppression appears to be associated with a modest but significantly increased, dose-dependent risk of early repeat ERC in LT patients with ABS. Prospective studies are needed to further investigate these findings and determine if sirolimus use or dose should potentially be reconsidered once ABS is diagnosed.
Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Colestase/cirurgia , Imunossupressores/efeitos adversos , Transplante de Fígado/efeitos adversos , Sirolimo/efeitos adversos , Cicatrização/efeitos dos fármacos , Adulto , Idoso , Anastomose Cirúrgica , Baltimore , Colangiopancreatografia Retrógrada Endoscópica/instrumentação , Colestase/diagnóstico por imagem , Colestase/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Reoperação , Estudos Retrospectivos , Fatores de Risco , Stents , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Recurrent biliary obstruction necessitating premature repeat endoscopic retrograde pancreatography (ERCP) remains a costly and morbid problem in patients undergoing treatment of post-orthotopic liver transplantation (OLT) biliary strictures. We evaluated the relationship between prednisone or sirolimus use and early recurrence of biliary obstruction given their negative effects on collagen production and cholangiocyte regeneration. METHODS: Medical records of adult patients who underwent OLT from 1998-2008 and developed anastomotic (ABS) and/or nonanastomotic (NABS) biliary strictures requiring endoscopic plastic stent therapy were reviewed. Outcome was early recurrence of biliary obstruction requiring repeat ERCP. Univariate and multivariable logistic regression analysis, adjusting for age, sex, and time from OLT to ERCP, were performed. RESULTS: 35 patients with ABS and 9 patients with NABS underwent a total of 157 ERCPs. Median patient age was 56 years, 68% were male, and hepatitis C was the most common OLT indication (52%). Early recurrence of biliary obstruction ocurred following 17.1% of ERCPs. In univariate analysis, neither prednisone nor sirolimus was associated with early recurrence of biliary obstruction. In multivariate analysis, however, sirolimus use was associated with increased incidence of early recurrent biliary obstruction (OR = 2.53; 95% CI: 0.77-8.32; p = 0.12); this was more pronounced at doses > 3 (OR = 4.27; 95% CI: 0.62-29.3; p = 0.14) than at ≤ 3 mg/day (OR = 2.24; 95% CI: 0.62-8.13; p = 0.22) and statistically significant in patients with ABS only (OR = 1.44 per mg increase in sirolimus dose; 95% CI 1.02-2.03; p = 0.037). CONCLUSIONS: Sirolimus use, particularly at higher doses and patients with ABS, may be associated with an increased risk of early recurrence of biliary obstruction requiring repeat ERCP for post-OLT biliary strictures. Additional studies are needed to further investigate these findings and elucidate other risk factors.
Assuntos
Colestase/terapia , Imunossupressores/efeitos adversos , Transplante de Fígado/imunologia , Sirolimo/efeitos adversos , Stents , Adulto , Idoso , Colangiopancreatografia Retrógrada Endoscópica , Colestase/epidemiologia , Colestase/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/uso terapêutico , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Sirolimo/uso terapêutico , Resultado do TratamentoRESUMO
Primary sclerosing cholangitis (PSC) is a chronic, progressive, inflammatory and obstructive disease of the intra- and extra-hepatic bile ducts of unknown etiology. Currently, orthotopic liver transplantation (OLT) is the only definitive treatment for PSC-related end-stage liver disease. However, PSC has been known to recur in the grafted liver. Roux-en-Y hepaticojejunostomy is more commonly performed than choledochocholedochostomy for PSC, although choledochocholedochostomy has been found to be safe and efficacious for PSC if the distal common bile duct is uninvolved at the time of OLT. Our case is unique in that it describes a patient who developed de-novo cholangiocarcinoma in the remnant portion of the native common bile duct six years after OLT with choledochocholedochostomy for PSC-associated end-stage liver disease without having PSC recurrence. In conclusion, our case report indicates that choledochocholedochostomy may not be desirable in PSC due to an increased risk of developing cholangiocarcinoma in the native common bile duct. This risk exists as well with a Roux-en-Y hepaticojejunostomy in the remaining intra-duodenal and intra-pancreatic biliary epithelium, although in theory to a lesser extent. Therefore, the risk of developing cholangiocarcinoma in the recipient common bile duct can only be completely eliminated by performing a Whipple procedure at the time of OLT.
Assuntos
Colangiocarcinoma/etiologia , Colangite Esclerosante/cirurgia , Neoplasias do Ducto Colédoco/etiologia , Transplante de Fígado/efeitos adversos , Biópsia , Colangiocarcinoma/diagnóstico , Colangiopancreatografia Retrógrada Endoscópica , Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/diagnóstico , Feminino , Humanos , Transplante de Fígado/métodos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Hepatitis C poses a substantial global health burden. Three to five percent of individuals with liver cirrhosis secondary to hepatitis C will develop hepatocellular carcinoma. The development of hepatocellular carcinoma is closely associated with cirrhosis in hepatitis C infection, whereas in hepatitis B virus infection, hepatocellular carcinoma may occur in the absence of cirrhosis. Although uncommon, hepatocellular carcinoma has been reported in hepatitis C patients without cirrhosis and, in very rare cases, in the absence of active viral replication. We report the case of a 51-year-old patient with hepatitis C who developed hepatocellular carcinoma in the absence of fibrosis and after having achieved sustained virological response with combination peginterferon and ribavirin therapy seven years prior. The patient successfully underwent surgical resection, and histopathological examination of the resected tissue demonstrated a poorly-differentiated hepatocellular carcinoma in an otherwise unremarkable liver. The patient continues to do well and has no evidence of tumor recurrence 18 months post-operatively. This case raises question regarding the carcinogenesis of hepatocellular carcinoma as a sequela of chronic hepatitis C in noncirrhotic liver and moreover after achieving sustained virological response.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Neoplasias Hepáticas/virologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia , Hepatite C/patologia , Humanos , Interferons/uso terapêutico , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Pessoa de Meia-Idade , Ribavirina/uso terapêutico , Resultado do Tratamento , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
Intrahepatic cholangiocarcinoma (ICCA) comprises 10% of all cholangiocarcinoma (CCA). It can be divided into three macroscopic subtypes, the least common of which is characterized by intraductal growth and believed to be more amenable to good outcomes with surgical resection compared to other ICCA. Recently, the rare finding of oncocytic differentiation has been described in this subtype and termed <