RESUMO
OBJECTIVE: The aim of our study was to assess the complications of hepatic fibrosis associated with bile duct ligation and the potential curative role of sepia ink extract in hepatic damage induced by bile duct ligation. METHODS: Rattus norvegicus rats were divided into 3 groups: Sham-operated group, model rats that underwent common bile duct ligation (BDL), and BDL rats treated orally with sepia ink extract (200 mg/kg body weight) for 7, 14, and 28 d after BDL. RESULTS: There was a significant reduction in hepatic enzymes, ALP, GGT, bilirubin levels, and oxidative stress in the BDL group after treatment with sepia ink extract. Collagen deposition reduced after sepia ink extract treatment as compared to BDL groups, suggesting that the liver was repaired. Histopathological examination of liver treated with sepia ink extract showed moderate degeneration in the hepatic architecture and mild degeneration in hepatocytes as compared to BDL groups. CONCLUSION: Sepia ink extract provides a curative effect and an antioxidant capacity on BDL rats and could ameliorate the complications of liver cholestasis.
Assuntos
Antioxidantes/farmacologia , Ductos Biliares/cirurgia , Colestase Extra-Hepática/prevenção & controle , Tinta , Sepia/química , Animais , Biomarcadores/sangue , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/etiologia , Colágeno/metabolismo , Fígado/metabolismo , Testes de Função Hepática , Masculino , Estresse Oxidativo , RatosRESUMO
AIM: To examine renal expression of organic anion transporter 5 (Oat5) and sodium-dicarboxylate cotransporter 1 (NaDC1), and excretion of citrate in rats with acute extrahepatic cholestasis. METHODS: Obstructive jaundice was induced in rats by double ligation and division of the common bile duct (BDL group). Controls underwent sham operation that consisted of exposure, but not ligation, of the common bile duct (Sham group). Studies were performed 21 h after surgery. During this period, animals were maintained in metabolic cages in order to collect urine. The urinary volume was determined by gravimetry. The day of the experiment, blood samples were withdrawn and used to measure total and direct bilirubin as indicative parameters of hepatic function. Serum and urine samples were used for biochemical determinations. Immunoblotting for Oat5 and NaDC1 were performed in renal homogenates and brush border membranes from Sham and BDL rats. Immunohistochemistry studies were performed in kidneys from both experimental groups. Total RNA was extracted from rat renal tissue in order to perform reverse transcription polymerase chain reaction. Another set of experimental animals were used to evaluate medullar renal blood flow (mRBF) using fluorescent microspheres. RESULTS: Total and direct bilirubin levels were significantly higher in BDL animals, attesting to the adequacy of biliary obstruction. An important increase in mRBF was determined in BDL group (Sham: 0.53 ± 0.12 mL/min per 100 g body weight vs BDL: 1.58 ± 0.24 mL/min per 100 g body weight, P < 0.05). An increase in the urinary volume was observed in BDL animals. An important decrease in urinary levels of citrate was seen in BDL group. Besides, a decrease in urinary citrate excretion (Sham: 0.53 ± 0.11 g/g creatinine vs BDL: 0.07 ± 0.02 g/g creatinine, P < 0.05) and an increase in urinary excretion of H(+) (Sham: 0.082 ± 0.03 µmol/g creatinine vs BDL: 0.21 ± 0.04 µmol/g creatinine, P < 0.05) were observed in BDL animals. We found upregulations of both proteins Oat5 and NaDC1 in brush border membranes where they are functional. Immunohistochemistry technique corroborated these results for both proteins. No modifications were observed in Oat5 mRNA and in NaDC1 mRNA levels in kidney from BDL group as compared with Sham ones. CONCLUSION: Citrate excretion is decreased in BDL rats, at least in part, because of the higher NaDC1 expression. Using the outward gradient of citrate generated by NaDC1, Oat5 can reabsorb/eliminate different organic anions of pathophysiological importance.
Assuntos
Colestase Extra-Hepática/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Icterícia Obstrutiva/metabolismo , Rim/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Animais , Bilirrubina/sangue , Biomarcadores/sangue , Biomarcadores/urina , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/genética , Colestase Extra-Hepática/urina , Ácido Cítrico/urina , Ducto Colédoco/cirurgia , Transportadores de Ácidos Dicarboxílicos/genética , Modelos Animais de Doenças , Icterícia Obstrutiva/sangue , Icterícia Obstrutiva/genética , Icterícia Obstrutiva/urina , Ligadura , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Ratos Wistar , Circulação Renal , Eliminação Renal , Simportadores/genética , Fatores de Tempo , Regulação para CimaRESUMO
Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models.
Assuntos
Ácidos e Sais Biliares/toxicidade , Colestase Extra-Hepática/patologia , Ácido Glicoquenodesoxicólico/toxicidade , Hepatócitos/efeitos dos fármacos , Icterícia Obstrutiva/patologia , Acetilação , Animais , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Células Cultivadas , Colestase Extra-Hepática/sangue , Relação Dose-Resposta a Droga , Proteína HMGB1/sangue , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Icterícia Obstrutiva/sangue , Queratina-18/sangue , Camundongos Endogâmicos C57BL , Necrose , Cultura Primária de Células , Especificidade da EspécieRESUMO
We report the case of late vitamin K deficiency bleeding (VLDB), with appropriate but insufficient prophylaxis, secondary to extrahepatic cholestasis. Late VKDB is rare today but serious, with a risk of intracranial hemorrhage in more than half of the cases. The diagnosis, causes and prevention of this disease are discussed.
Assuntos
Colestase Extra-Hepática/complicações , Sangramento por Deficiência de Vitamina K/etiologia , Dorso , Ácidos e Sais Biliares/sangue , Bilirrubina/sangue , Aleitamento Materno , Maus-Tratos Infantis/diagnóstico , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/diagnóstico , Diagnóstico Diferencial , Hematoma/etiologia , Humanos , Lactente , Testes de Função Hepática , Masculino , Adesão à Medicação , Vitamina D/administração & dosagem , Vitamina D/sangue , Vitamina K/administração & dosagem , Vitamina K/sangue , Sangramento por Deficiência de Vitamina K/sangue , Sangramento por Deficiência de Vitamina K/diagnóstico , Sangramento por Deficiência de Vitamina K/prevenção & controleRESUMO
BACKGROUND: Bile duct ligation (BDL) is a commonly used cholestatic liver disease (CLD) model. We recently found that L-arginine levels were significantly raised by melatonin in young rats with BDL. We hypothesized that protein kinase C-α (PKC-α) is involved in the increases of L-arginine in melatonin-treated BDL rats. In addition, we tested whether melatonin prevents nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced reactive oxygen species (ROS) production, in rats with BDL, through PKC. METHODS: Four groups of young male rats were studied: shams (n = 6), untreated BDL rats (n = 9), melatonin-treated shams (n = 6, M), and melatonin-treated BDL rats (n = 6, BDL + M). Melatonin-treated rats received daily melatonin 1 mg/kg/d via i.p. injection. All surviving rats were killed 14 d after surgery. RESULTS: Melatonin prevented BDL-induced mortality and kidney injury. Melatonin additionally increased L-arginine concentrations in BDL liver, which is correlated with decreased PKC-α translocation. Next, melatonin increased L-arginine levels in BDL kidneys, which was correlated with decreased renal levels of arginase II. In the BDL kidney, melatonin decreased PKC-ß translocation, reduced p47phox translocation, and diminished NADPH-dependent superoxide production. CONCLUSION: Melatonin inhibits PKC-α to increase cationic amino acid transporter-1 (CAT-1)-mediated L-arginine uptake in BDL liver, whereas it inhibits PKC-ß to reduce NADPH-dependent superoxide production.
Assuntos
Arginina/metabolismo , Colestase Extra-Hepática/tratamento farmacológico , Ducto Colédoco/cirurgia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Melatonina/farmacologia , NADPH Oxidases/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Arginase/metabolismo , Arginina/análogos & derivados , Arginina/sangue , Transporte Biológico , Transportador 1 de Aminoácidos Catiônicos/metabolismo , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/enzimologia , Colestase Extra-Hepática/etiologia , Modelos Animais de Doenças , Feminino , Injeções Intraperitoneais , Rim/enzimologia , Ligadura , Fígado/enzimologia , Masculino , Melatonina/administração & dosagem , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C beta , Proteína Quinase C-alfa/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Transporte Proteico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
CONTEXT: The root of Platycodon grandiflorum (Jacq.) A. DC. (Campanulaceae) has been widely studied for its hepatoprotective effects against various hepatotoxicants. OBJECTIVE: The present study evaluated the protective effect of the standardized aqueous extract of P. grandiflorum (BC703) on cholestasis-induced hepatic injury in mice. MATERIALS AND METHODS: BC703 is a standardized aqueous extract of P. grandiflorum in reference to platycodin D (at least 0.8%). The mice were allocated into five groups as follows: Sham-operated, bile duct ligation (BDL) alone, and BDL with BC703 (1, 5, and 10 mg/kg BW) treated group. BC703 was given for 3 consecutive days before BDL operation. The animals were sacrificed by CO2 anesthesia post-24 h of BDL operations. RESULTS AND DISCUSSION: Serum alanine aminotransferase and serum aspartate aminotransferase increased to 395.2 ± 90.0 and 266.0 ± 45.6 Unit/L in the BDL alone group and decreased with BC703 in a dose-dependent manner. Especially the 10 mg/kg of BC703-treated mice showed a 77% decrease of serum alanine aminotransferase and 56% of aspartate aminotransferase as compared with BDL alone. Decreased antioxidant enzyme levels in BDL alone group were elevated in BC703-treated groups ranging from 7 to 29% for glutathione and from 13 to 25% for superoxide dismutase. BC703 treatment also attenuated malondialdehyde (from 3 to 32%) and nitric oxide levels (from 32 to 50%) as compared with BDL alone. Histopathological studies further confirmed the hepatoprotective effect of BC703 in BDL-induced cholestesis. CONCLUSION: BC703 could attenuate liver injury by BDL in mice, and test results indicate that BC703 might be useful in cholestatic liver injury.
Assuntos
Colestase Extra-Hepática/tratamento farmacológico , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Platycodon , Substâncias Protetoras/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/patologia , Cromatografia Líquida de Alta Pressão , Ducto Colédoco/cirurgia , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Ligadura , Fígado/enzimologia , Fígado/patologia , Hepatopatias/sangue , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Raízes de Plantas , Plantas Medicinais , Platycodon/química , Substâncias Protetoras/análise , Substâncias Protetoras/isolamento & purificação , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de TempoRESUMO
We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in "-omics" and other studies using biomarkers.
Assuntos
Biomarcadores Tumorais/sangue , Colestase Extra-Hepática/sangue , Fígado/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Colestase Extra-Hepática/etiologia , Humanos , Fígado/enzimologia , Análise Multivariada , Estadiamento de Neoplasias , Pâncreas/enzimologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Análise de Regressão , gama-Glutamiltransferase/sangueRESUMO
Mitochondria are known to be involved in cholestatic liver injury. The potential protective effect of resveratrol in cholestatic liver injury and the possible roles of autophagy and apoptosis induction in this process are not yet clear. The aim of this study is to determine whether resveratrol administration after bile duct ligation can reduce cholestasis-induced liver injury through modulating apoptosis, mitochondrial biogenesis and autophagy. A rat model of cholestasis was established by bile duct ligation (BDL) and compared with a sham group receiving laparotomy without BDL, with resveratrol or control treatments following BDL. The expression of proteins involved in the apoptotic and autophagic pathways were analyzed by western blotting. Apoptosis was examined by TUNEL staining. In the resveratrol/BDL group LC3-II upregulation persisted for 1-7 days, Bax was downregulated and catalase was upregulated at 3-7 days after resveratrol treatment. The decline in mitochondrial DNA copy number was reversed at 3-7 days. Caspase 3 expression was significantly downregulated at 3-7 days in the resveratrol group. TUNEL staining showed significant numbers of apoptotic liver cells appeared in livers 3-7 days after BDL and that was decreased by resveratrol treatment. Our results indicate that early resveratrol treatment reverses impaired liver function within hours of BDL.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Colestase Extra-Hepática/tratamento farmacológico , Mitocôndrias Hepáticas/efeitos dos fármacos , Estilbenos/farmacologia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Antioxidantes/uso terapêutico , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Caspase 3/metabolismo , Catalase/metabolismo , Colestase Extra-Hepática/sangue , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias Hepáticas/fisiologia , Ratos , Ratos Sprague-Dawley , Resveratrol , Transdução de Sinais , Estilbenos/uso terapêutico , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Cholestatic liver diseases can be caused by genetic defects, drug toxicities, hepatobiliary malignancies or obstruction of the biliary tract. Cholestasis leads to accumulation of bile acids (BAs) in hepatocytes. Direct toxicity of BAs is currently the most accepted hypothesis for cholestatic liver injury. However, information on which bile acids are actually accumulating during cholestasis is limited. AIM: To assess the BA composition in liver and serum after bile duct ligation (BDL) in male C57Bl/6 mice between 6 h and 14 days and evaluate toxicity of the most abundant BAs. RESULTS: Bile acid concentrations increased in liver (27-fold) and serum (1400-fold) within 6 h after surgery and remained elevated up to 14 days. BAs in livers of BDL mice became more hydrophilic than sham controls, mainly because of increased 6ß-hydroxylation and taurine conjugation. Among the eight unconjugated and 16 conjugated BAs identified in serum and liver, only taurocholic acid (TCA), ß-muricholic acid (ßMCA) and TßMCA were substantially elevated representing >95% of these BAs over the entire time course. Although glycochenodeoxycholic acid and other conjugated BAs increased in BDL animals, the changes were several orders of magnitude lower compared with TCA, ßMCA and TßMCA. A mixture of these BAs did not cause apoptosis or necrosis, but induced inflammatory gene expression in cultured murine hepatocytes. CONCLUSION: The concentrations of cytotoxic BAs are insufficient to cause hepatocellular injury. In contrast, TCA, ßMCA and TßMCA are able to induce pro-inflammatory mediators in hepatocytes. Thus, BAs act as inflammagens and not as cytotoxic mediators after BDL in mice.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase Extra-Hepática/sangue , Fígado/metabolismo , Animais , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/farmacologia , Ductos Biliares Extra-Hepáticos/cirurgia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Mediadores da Inflamação/metabolismo , Ligadura , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismoRESUMO
A total of 11 prospective cases of endoscopic ultrasound (EUS)-guided cholangio-drainage (EUCD) in patients with end-stage biliopancreatic cancer and biliary tract obstruction are reported. Other available drainage methods (endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic biliary drainage) of the biliary tract were attempted without success prior to EUS. Technical and clinical success was achieved in 10/11 patients (91%) and in 9/10 patients (90%), respectively. Bilirubin decreased by more than 50% in 7/11 patients (64%). One patient had a complication that required re-intervention and another patient developed biloma. No mortality directly related to the procedure was documented. In conclusion, EUCD is a good alternative for patients with malignant obstruction of the biliary tract in whom other drainage methods have failed.
Assuntos
Colestase Extra-Hepática/terapia , Neoplasias do Sistema Digestório/complicações , Drenagem , Ultrassonografia de Intervenção , Adulto , Idoso , Idoso de 80 Anos ou mais , Bilirrubina/sangue , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Stents , Adulto JovemRESUMO
This report describes extrahepatic bile duct obstruction in two ferrets, which were presented with anorexia, chronic weight loss and general weakness. Physical examination revealed lethargy, cachexia, dehydration, abdominal pain and icterus. Marked haematological, serum chemistry and urinalysis abnormalities included hyperbilirubinaemia (65·5 and 114·2 µmol/L), high concentrations of alanine transaminase (1327·53 and 2578·88 IU/L) and biluribinuria. Abdominal ultrasonography revealed thickening of the bile duct together with the gall bladder wall. The common bile duct was obviously distended. Choledochotomy revealed inspissated bile with fragile green gelatinous plugs that was removed to allow the bile to flow into the duodenum. Cytology and culture of the biliary tract contents were negative for bacteria. Laboratory analyses of biliary plugs showed presence of only protein substances, without detectable mineral composition. Histopathological examination of the liver showed diffuse steatosis and non-specific cholangiohepatitis in both cases.
Assuntos
Colestase Extra-Hepática/veterinária , Furões , Animais , Análise Química do Sangue/veterinária , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/diagnóstico , Colestase Extra-Hepática/cirurgia , Feminino , Laparotomia/veterinária , Masculino , Prognóstico , Resultado do TratamentoRESUMO
OBJECTIVE: Cystatin C is a very potent inhibitor of cysteine proteinases and, it has been clinically applied as a sensitive marker in monitoring of renal and liver functions. The aim of this study was to reveal whether cystatin C may be a useful marker for distinguishing intra- versus extrahepatic cholestasis. MATERIALS AND METHODS: Serum cystatin C concentrations were determined by nephelometric immunoassay using N latex cystatin C kit in 53 patients with cholestatic disorder that included 18 patients with intrahepatic cholestasis , 17 patients with malignant extrahepatic cholestasis , 18 patients with benign extrahepatic cholestasis. Serum cystatin C concentration was also determined in 20 healthy volunteers. RESULTS: Mean serum cystatin C concentration was 2.82 +/- 0.24 mg/l (SD) in patients with intrahepatic cholestasis, 2.05 +/- 0.15 mg/l in patients with extrahepatic malignant cholestasis, 1.37 +/- 0.13 mg/l in extrahepatic benign cholestatic patients and 0.93 +/- 0.24 mg/l in control group. Serum cystatin C concentrations in patients with cholestatic disease were significantly higher than those in the healthy controls (p < 0.001). Moreover, mean serum cystatin C concentration in patients with intrahepatic cholestasis was higher than those in extrahepatic cholestasis groups (p < 0.001). Serum cystatin C concentrations were significantly higher in patients with malignant xtrahepatic cholestasis than in patients with benign extrahepatic cholestasis p < 0.001). There were no correlations patients among serum cystatin C concentrations and serum levels of AST, ALT, ALP, GGT, total and conjugated bilirubin. CONCLUSION: Our results suggested that serum cystatin C level may be a potential biochemical marker both to point out an intrahepatic origin by excluding an extrahepatic source of cholestasis in patients with jaundice and to possibly differentiate bening and malignant extrahepatic cholestatic disorders.
Assuntos
Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/diagnóstico , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/diagnóstico , Cistatina C/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Acute obstructive cholangitis is a common disease with a high mortality rate. Ligands for peroxisome proliferator-activated receptor-gamma (PPARgamma), such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15D-PGJ(2)), have been proposed as a new class of anti-inflammatory compounds. This study investigated the effect of 15D-PGJ(2) treatment on lipopolysaccharide (LPS)-induced acute obstructive cholangitis. The rats were randomly assigned to five groups: sham operation (Sham; simple laparotomy), sham operation with intraperitoneal saline infusion (Sham+Saline), sham operation with intraperitoneal LPS infusion (Sham+LPS), bile duct ligation (BDL) with saline infusion into the bile duct (BDL+Saline), and BDL with LPS infusion into the bile duct (BDL+LPS). Biochemical assays of blood samples, histology of the liver, portal venous pressure, hyaluronic acid clearance, and expression of inflammation-associated genes in the liver were evaluated. Furthermore, the Sham+LPS and the BDL+LPS group were divided into two groups (with and without 15D-PGJ(2) treatment), and their survival rates were compared. Biochemical assays of blood samples, portal venous pressure, hyaluronic acid clearance, and expression of inflammation-associated genes in the liver were all significantly higher in the BDL+LPS group compared with those in the BDL+Saline group, indicating the presence of increased liver damage in the first group. However, preoperative administration of 15D-PGJ(2) significantly improved these outcomes. Furthermore, the survival rate after establishment of cholangitis was significantly improved by the administration of 15D-PGJ(2) in the BDL+LPS group. These results clearly demonstrate that 15D-PGJ(2) inhibits the inflammatory response and endothelial cell damage seen in acute obstructive cholangitis and could contribute to improve the outcome of this pathology.
Assuntos
Colangite/prevenção & controle , Colestase Extra-Hepática/complicações , Endotélio Vascular/efeitos dos fármacos , Falência Hepática Aguda/prevenção & controle , Prostaglandina D2/análogos & derivados , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Ductos Biliares/cirurgia , Bilirrubina/sangue , Colangite/sangue , Colangite/induzido quimicamente , Colangite/complicações , Colangite/patologia , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/patologia , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Ácido Hialurônico/sangue , Ácido Hialurônico/metabolismo , Interleucina-6/genética , Ligadura , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Circulação Hepática/fisiologia , Falência Hepática Aguda/etiologia , Masculino , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo III/genética , PPAR gama/genética , Prostaglandina D2/farmacologia , Prostaglandina D2/uso terapêutico , Ratos , Ratos Wistar , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genéticaRESUMO
UNLABELLED: Fibroblast growth factor 19 (FGF19) is an endocrine factor produced by the small intestine in response to uptake of luminal bile salts. In the liver, FGF19 binds to FGF receptor-4, resulting in down-regulation of cytochrome P (CYP) 7A1 and reduced bile salt synthesis. Down-regulation of CYP7A1 under cholestatic conditions has been attributed to bile salt-mediated induction of the transcriptional repressor short heterodimer partner (SHP), because the interrupted enterohepatic cycle of bile salts is thought to abrogate intestinal FGF19 production and thus result in lowering of plasma FGF19 levels. Unexpectedly, we observed marked elevation of plasma FGF19 in patients with extrahepatic cholestasis caused by a pancreatic tumor (2.3 +/- 2.3 in cholestatic versus 0.40 +/- 0.25 ng/mL and 0.29 +/- 0.12 ng/mL in postcholestatic patients who received preoperative drainage by biliary stenting, P = 0.004, and noncholestatic control patients, P = 0.04, respectively). Although FGF19 messenger RNA (mRNA) is virtually absent in normal liver, FGF19 mRNA was strongly increased (31-fold to 374-fold, P < 0.001) in the liver of cholestatic patients in comparison with drained and control patients. In the absence of changes in SHP mRNA, CYP7A1 mRNA was strongly reduced (7.2-fold to 24-fold, P < 0.005) in the liver of cholestatic patients in comparison with drained and control patients, indicating an alternative regulatory pathway. Alterations in transcripts encoding hepatobiliary transporters [adenosine triphosphate-binding cassette, subfamily C, member 3 (ABCC3)/multidrug resistance protein 3 (MRP3), organic solute transporter alpha/beta (OSTalpha/beta), organic anion-transporting polypeptide (OATP1B1)] further suggest that bile salts are secreted via a nonbiliary route in patients with extrahepatic cholestasis. CONCLUSION: The liver expresses FGF19 under conditions of extrahepatic cholestasis. This is accompanied by a number of adaptations aimed at protecting the liver against bile salt toxicity. FGF19 signaling may be involved in some of these adaptations.
Assuntos
Adaptação Fisiológica , Colestase Extra-Hepática/sangue , Colesterol 7-alfa-Hidroxilase/metabolismo , Neoplasias do Ducto Colédoco/complicações , Fatores de Crescimento de Fibroblastos/sangue , Adulto , Idoso , Ácidos e Sais Biliares/biossíntese , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/fisiopatologia , Feminino , Regulação da Expressão Gênica , Homeostase , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
There were studied the results, termed from 12 to 24 months, of operatively treated patients for subhepatic cholestasis of nontumoral etiology. The general clinical examination, ultrasonographic investigation were performed to the patients, as well as morphological changes estimation in hepatic fine-needle biopsies samples, biochemical indices and the state of systemic hepatic blood circulation. Application of complex staged operative interventions, added by hepatoregenerative operations, have had favored normalization of laboratory indices and structural hepatic changes as well as the hepatic blood supply improvement due to systolic inflow enhancement by 26% and microcirculatory bed blood circulation -- by 51%.
Assuntos
Colestase Extra-Hepática/cirurgia , Hepatectomia/métodos , Fígado/cirurgia , Bilirrubina/sangue , Biópsia por Agulha Fina , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/diagnóstico por imagem , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/patologia , Circulação Hepática/fisiologia , Testes de Função Hepática , Regeneração Hepática/fisiologia , Resultado do Tratamento , UltrassonografiaRESUMO
BACKGROUND AND AIM: The precise mechanism of bile regurgitation from the biliary system to the blood stream still remains to be elucidated. The aim of this study was to examine the initial site of bile regurgitation in vivo after common bile duct (CBD) obstruction by digitally enhanced fluorescence microscopy. METHODS: The fluorescence excreted into bile canaliculi after the administration of sodium fluorescein was continuously observed in CBD obstruction, using video-enhanced contrast (VEC) microscopy equipped with a silicon intensified target (SIT) camera. The liver histology and the localization of Mg(2+)-ATPase were examined by light and electron microscopy. RESULTS: By the continuous recording of canalicular fluorescence, the sequential regurgitation of the fluorescence from the canaliculi to the hepatocyte cytoplasm to the sinusoids was distinctively recognized after CBD obstruction. Bile canalicular fluorescence was enhanced, and then the fluorescence of the hepatocyte cytoplasm increased in intensity, followed by regurgitation of the fluorescence to the sinusoids. These in vivo sequences closely correlated with changes in CBD pressure. In zone 1, canalicular fluorescence focally burst into hepatocyte cytoplasm, thus resulting in the formation of fluorescent cells. By light and electron microscopy, the fluorescent cells were found to correspond to the liver cell injury. The reaction products of Mg(2+)-ATPase were incorporated into vesicles with a decreased canalicular activity, and then were transported to the sinusoidal surface after CBD obstruction. CONCLUSIONS: The initial site of bile regurgitation may be transcellular, and partly involves liver cell injury in zone 1 in extrahepatic biliary obstruction, associated with increased pressure of the biliary system.
Assuntos
Canalículos Biliares/metabolismo , Bile/metabolismo , Colestase Extra-Hepática/metabolismo , Fígado/metabolismo , Microscopia de Fluorescência , Microscopia de Vídeo/métodos , Animais , Canalículos Biliares/enzimologia , Canalículos Biliares/ultraestrutura , Vasos Sanguíneos/metabolismo , ATPase de Ca(2+) e Mg(2+)/metabolismo , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/patologia , Citoplasma/metabolismo , Modelos Animais de Doenças , Feminino , Fluoresceína , Corantes Fluorescentes , Hepatócitos/metabolismo , Fígado/ultraestrutura , Microscopia Eletrônica , Ratos , Ratos Wistar , Processamento de Sinais Assistido por Computador , Fatores de TempoRESUMO
BACKGROUND: Cholestasis, roughly divided into intrahepatic and extrahepatic forms, is a clinical challenge. Extrahepatic cholestasis, characterized by dilated bile ducts, is caused by either a bile duct stone or stricture, with stricture most often related to a malignancy. The aim of the present study was to analyze the value of common liver function tests in separating patients with malignant bile duct strictures from those with stones. METHODS: All consecutive patients admitted for endoscopic retrograde cholangiopancreatography (ERCP) were included in the study population if a bile duct stricture related to a malignancy was found by ERCP (n=103) or if a bile duct stone was successfully extracted during ERCP, thus confirming the diagnosis of a stone (n=109). Plasma alkaline phosphatase, gamma-glutamyltransferase, alanine aminotransferase and bilirubin values were determined in the morning before ERCP. RESULTS: Plasma bilirubin (p<0.001), alkaline phosphatase (p<0.001) and alanine aminotransferase (p=0.040) levels were significantly higher in patients with malignant bile duct strictures than in those with bile duct stones. In addition, gamma-glutamyltransferase levels seemed to be higher in patients with malignant strictures than in those with stones, although the difference did not reach statistical significance (p=0.053). In receiver operating characteristic analyses, bilirubin proved to be the best laboratory test in differentiating patients (p=0.001 vs. alkaline phosphatase, p<0.001 vs. alanine aminotransferase and p<0.001 vs. gamma-glutamyltransferase). With a plasma bilirubin cutoff value of 145 micromol/L, four out of five patients were categorized correctly. CONCLUSIONS: Plasma bilirubin seems to be the best liver function test in distinguishing patients with malignant bile duct strictures from those with bile duct stones. This routine test should receive more attention in clinical decision-making than has previously been given.
Assuntos
Neoplasias dos Ductos Biliares/complicações , Cálculos/complicações , Colestase Extra-Hepática/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Neoplasias dos Ductos Biliares/sangue , Bilirrubina/sangue , Biomarcadores/sangue , Cálculos/sangue , Colangiopancreatografia Retrógrada Endoscópica , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/diagnóstico , Feminino , Humanos , Fígado/patologia , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Fatores Sexuais , gama-Glutamiltransferase/sangueRESUMO
CA 19-9 is a marker of malignancy of the pancreas and biliary tract. We report the case of a patient who had significantly elevated serum CA 19-9 levels and imaging studies suggestive of malignancy. On laparotomy, the patient was found to have Mirizzi syndrome, an uncommon cause of biliary obstruction from an impacted gallstone. This case illustrates that elevated serum CA 19-9 levels must be interpreted cautiously in cases of biliary obstruction.
Assuntos
Antígeno CA-19-9/sangue , Coledocolitíase/sangue , Colestase Extra-Hepática/sangue , Biomarcadores/sangue , Biópsia por Agulha , Colangiocarcinoma/diagnóstico , Coledocolitíase/diagnóstico , Coledocolitíase/cirurgia , Colestase Extra-Hepática/diagnóstico , Colestase Extra-Hepática/etiologia , Diagnóstico Diferencial , Neoplasias da Vesícula Biliar/diagnóstico , Humanos , Icterícia Obstrutiva/complicações , Icterícia Obstrutiva/diagnóstico , Icterícia Obstrutiva/cirurgia , Laparotomia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Síndrome , Tomografia Computadorizada por Raios XRESUMO
Acute cholestasis is associated with increased activity of the endogenous opioid system. It is also known that opioid receptor agonists like morphine decrease the intestinal transit. The purpose of the present study was to investigate the effect of cholestasis on the small intestine transit and the possible involvement of opioid system in this phenomenon in mice. Cholestasis was induced by bile duct-ligation and intestinal transit was measured with charcoal meal and calculation of percent of transit through small intestine. The effect of chronic administration of naltrexone and acute pretreatment with morphine on intestinal transit was evaluated in bile duct-ligated (BDL) as well as unoperated (CTL) and sham-operated (SHAM) animals. The plasma alkaline phosphatase and alanine aminotransferase activities were also measured. A significant decrease in small intestine transit (%transit) was observed in BDL mice compared to SHAM animals, which was prominent even after 24 h of cholestasis. Chronic pretreatment with an opioid receptor antagonist, naltrexone, (10 mg/kg, i.p for 2, 4 or 6 days) completely restored the cholestasis-induced decrease in %transit to that of control animals. Although the acute administration of morphine (2 mg/kg, s.c.) 20 min before charcoal feeding caused a significant decrease in the intestinal transit of CTL and SHAM animals, it did not decrease the %transit of BDL animals on the day 5 after operation. Our findings show that acute cholestasis is associated with a prominent decrease in small intestine transit in mice and opioid receptors maybe involved in this phenomenon.
Assuntos
Colestase Extra-Hepática/tratamento farmacológico , Colestase Extra-Hepática/fisiopatologia , Trânsito Gastrointestinal/efeitos dos fármacos , Morfina/uso terapêutico , Naltrexona/uso terapêutico , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/complicações , Modelos Animais de Doenças , Quimioterapia Combinada , Injeções Intraperitoneais , Injeções Subcutâneas , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos , Morfina/administração & dosagem , Naltrexona/administração & dosagemRESUMO
An experimental model of microsurgical cholestasis is studied as an alternative to the most frequently used surgical techniques, based on the section of the common bile duct. This microsurgical technique consists of the resection of the extrahepatic biliary tract, that is, of the common bile duct in continuity with the bile ducts that drain the four lobes of the rat liver. At 30 days of evolution, rats with microsurgical cholestasis do not develop biliary pseudocysts or intraperitoneal hilar hepatopulmonary abscesses and show an increase (p < 0.001) in total bilirubin (9.50 +/- 1.50 mg/dL vs. 1.60 +/- 0.35 mg/dL), bile acids (225 +/- 87 micromol/L vs. 12.5 +/- 14.50 micromol/L), gamma-glutamyltranspeptidase (375 +/- 143 U/L vs. 8 +/- 11 U/L), and alkaline phosphatase (73 +/- 25 U/L vs. 23 +/- 4 U/L) levels. The histological study shows fibrosis with biliary proliferation. The microsurgical cholestasis technique is a valid alternative to other techniques and can be an adequate experimental model for the study of etiopathogenic mechanisms of obstructive jaundice and especially to study extrahepatic biliary atresia.