RESUMO
Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.
Assuntos
Pancreatite Crônica/diagnóstico , HumanosRESUMO
Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.
Assuntos
Pancreatite Crônica/terapia , Árvores de Decisões , Humanos , Apoio NutricionalRESUMO
UNLABELLED: Patients with cirrhosis receiving norfloxacin show a restored inflammatory balance that likely prevents clinical complications derived from an excessive proinflammatory response to bacterial product challenges. This study sought to investigate associated inflammatory control mechanisms established in patients with cirrhosis receiving norfloxacin. A total of 62 patients with cirrhosis and ascites in different clinical conditions were considered. Blood samples were collected and intracellular and serum norfloxacin were measured. Inflammatory mediators were evaluated at messenger RNA and protein levels. Neutrophils from all patients were cultured with lipopolysaccharide (LPS) and anti-interleukin-10 (anti-IL-10) monoclonal antibody in different conditions. IL-10 and heme oxygenase-1 (HO-1) were up-regulated in patients receiving norfloxacin and correlated with norfloxacin in a concentration-dependent manner, whereas proinflammatory inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-κB behaved inversely. Higher IL-10 levels correlated with lower white blood cell count and higher mean arterial pressure. No correlations were found between IL-10 and disease clinical scores or liver function markers in blood. Neutrophilic in vitro assays showed that the effect of LPS on proinflammatory mediator levels in the presence of norfloxacin was abrogated by significantly increasing IL-10 and HO-1 expression. After stimulation with LPS plus anti-IL-10, proinflammatory mediators were dramatically increased in patients receiving norfloxacin, and increasing intracellular norfloxacin concentrations did not decrease the expression levels of these proinflammatory molecules. Unblocking IL-10 restored proinflammatory mediator and HO-1 expression to previously observed levels in response to LPS stimulation. CONCLUSION: Although the described association does not necessarily mean causality, an IL-10-mediated HO-1-induced anti-inflammatory mechanism is present in patients with cirrhosis receiving norfloxacin, that is directly associated with cell-modulating events in these patients.
Assuntos
Heme Oxigenase-1/fisiologia , Interleucina-10/fisiologia , Cirrose Hepática/tratamento farmacológico , Norfloxacino/uso terapêutico , Idoso , Anticorpos Monoclonais/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , DNA Bacteriano/sangue , Regulação para Baixo , Feminino , Heme Oxigenase-1/sangue , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-10/sangue , Interleucina-10/imunologia , Contagem de Leucócitos , Lipopolissacarídeos/farmacologia , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II , Norfloxacino/sangue , Peritonite/prevenção & controle , Estudos Prospectivos , Regulação para CimaRESUMO
OBJECTIVES: Although aggressive fluid therapy during the first days of hospitalization is recommended by most guidelines and reviews on acute pancreatitis (AP), this recommendation is not supported by any direct evidence. We aimed to evaluate the association between the amount of fluid administered during the initial 24 h of hospitalization and the incidence of organ failure (OF), local complications, and mortality. METHODS: This was a prospective cohort study. We included consecutive adult patients admitted with AP. Local complications and OF were defined according to the Atlanta Classification. Persistent OF was defined as OF of >48-h duration. Patients were divided into three groups according to the amount of fluid administered during the initial 24 h: group A: <3.1 l (less than the first quartile), group B: 3.1-4.1 l (between the first and third quartiles), and group C: >4.1 l (more than the third quartile). RESULTS: A total of 247 patients were analyzed. Administration of >4.1 l during the initial 24 h was significantly and independently associated with persistent OF, acute collections, respiratory insufficiency, and renal insufficiency. Administration of <3.1 l during the initial 24 h was not associated with OF, local complications, or mortality. Patients who received between 3.1 and 4.1 l during the initial 24 h had an excellent outcome. CONCLUSIONS: In our study, administration of a small amount of fluid during the initial 24 h was not associated with a poor outcome. The need for a great amount of fluid during the initial 24 h was associated with a poor outcome; therefore, this group of patients must be carefully monitored.
Assuntos
Hidratação , Pancreatite Necrosante Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Medicina Baseada em Evidências , Feminino , Hidratação/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Necrosante Aguda/etiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
UNLABELLED: Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(-) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(-) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. CONCLUSION: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction.
Assuntos
Infecções Bacterianas/fisiopatologia , Translocação Bacteriana , DNA Bacteriano/metabolismo , Hemodinâmica , Circulação Hepática/fisiologia , Cirrose Hepática/fisiopatologia , Fígado/fisiopatologia , Adulto , Idoso , Ascite/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Resistência VascularRESUMO
BACKGROUND: Bacterial infections are common complications arising in patients with cirrhosis and ascites. Translocation of bacterial DNA is a dynamic process that is associated with an increased inflammatory response and a poor prognosis in this setting. The aim of this study was to study whether peritoneal macrophages remain in a chronic primed status to allow a rapid response to subsequent events of bacterial translocation. PATIENTS AND METHODS: Peritoneal monocyte-derived macrophages were isolated from 25 patients with cirrhosis and non-infected ascites and compared with donor's blood monocytes. Activation cell-surface markers were screened using flow-cytometry, and the phosphorylation state of ERK 1/2, p38 MAP Kinase, PKB/Akt and transcription factors c-Jun and p65 NFκB were evaluated using Western blot. Synthesis of tumour necrosis factor alpha, interleukin 6 (IL-6) and interleukin-10 (IL-10) at baseline and in response to bacterial stimuli was evaluated using ELISA. RESULTS: A high expression of CD54, CD86 and HLA-DR at baseline was displayed by peritoneal macrophages. Increased phosphorylated levels of ERK1/2, protein kinase B (PKB) and c-Jun, together with IL-6 production, were observed in peritoneal macrophages at baseline compared with donors' blood monocytes. A positive correlation was established between basal IL-6 levels and extracellular signal-regulated kinase (ERK) phosphorylation in peritoneal macrophages from patients with cirrhosis (r=0·9; P=0·005). Addition of lipopolysaccharide induced higher phosphorylation levels of all studied signalling intermediates than synthetic-oligodeoxydinucleotides, but similar end-stage p65 NFκB. CONCLUSIONS: A sustained immune response is present in ascitic fluid of cirrhotic patients, even in the temporal absence of bacterial antigens. This would facilitate a fast response, probably controlled by IL-6, against repeated bacterial-DNA translocation or in liver chronic inflammation.
Assuntos
Líquido Ascítico/imunologia , Translocação Bacteriana/imunologia , Cirrose Hepática/imunologia , Macrófagos Peritoneais/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Adulto , Idoso , Citocinas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Fosforilação , Estudos ProspectivosRESUMO
Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt.
Assuntos
Procedimentos Endovasculares/métodos , Encefalopatia Hepática/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Complicações Pós-Operatórias/cirurgia , Ascite/tratamento farmacológico , Ascite/etiologia , Procedimentos Endovasculares/instrumentação , Desenho de Equipamento , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/cirurgia , Furosemida/uso terapêutico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Encefalopatia Hepática/etiologia , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/cirurgia , Veias Jugulares , Circulação Hepática , Cirrose Hepática Alcoólica/complicações , Masculino , Pessoa de Meia-Idade , Politetrafluoretileno , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Derivação Portossistêmica Transjugular Intra-Hepática/instrumentação , Complicações Pós-Operatórias/etiologia , Propranolol/uso terapêutico , Reoperação , Espironolactona/uso terapêutico , StentsRESUMO
UNLABELLED: The aim of our study was to investigate the dynamics of brain water content assessed by magnetic resonance imaging (MRI) applications in patients with cirrhosis and overt episodic hepatic encephalopathy (HE). METHODS: Twenty-four patients with cirrhosis and overt HE, 9 healthy controls and 9 controls with cirrhosis but without HE were included. All patients underwent laboratory analysis, MRI and (1)H MRS in the first 24h after the diagnosis of encephalopathy. Five of them were studied again 5days after the resolution of HE. RESULTS: The values of glutamine/glutamate (Glx) increased progressively (healthy controls: 1.8; cirrhotic controls: 2.4; HE: 4.4; p=0.0001). Values of myo-inositol were lower among cirrhotics than in healthy controls (healthy: 0.6; cirrhotic: 0.3; HE: 0.4; p=0.01). Patients with overt HE showed a decrease in MTR in several brain locations. A significant correlation was observed between MTR values and Glx/creatine ratios (r=-0.54; P=0.004). Five days after the resolution of HE, there were no changes in brain Glx/Cr or MTR but a significant decrease of median ADC in parietal grey matter was observed (acute HE: 121.9 vs. 5days later: 100.5; p<0.05). CONCLUSIONS: Cirrhotic patients with overt HE have a disturbance in the brain osmolyte homeostasis, reflecting a low-grade brain edema. Shortly after the clinical resolution of the episode of HE low-grade brain edema still persists, but there is a decrease in the ADC value in the parietal grey matter, suggesting water flux from extracellular to intracellular compartments and the existence of a vasogenic brain edema.
Assuntos
Edema Encefálico/metabolismo , Encéfalo/metabolismo , Encefalopatia Hepática/metabolismo , Água Corporal/metabolismo , Encéfalo/patologia , Edema Encefálico/complicações , Edema Encefálico/patologia , Estudos de Casos e Controles , Imagem de Tensor de Difusão , Feminino , Fibrose/complicações , Fibrose/metabolismo , Fibrose/patologia , Encefalopatia Hepática/complicações , Encefalopatia Hepática/patologia , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas Amielínicas/metabolismo , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Estudos Prospectivos , Prótons , Fatores de TempoRESUMO
BACKGROUND & AIMS: Patients with cirrhosis undergoing selective intestinal decontamination with norfloxacin show a reduction in serum cytokine levels, probably because of a combined effect of norfloxacin on bowel flora and neutrophils. METHODS: Thirty-one patients with cirrhosis receiving norfloxacin (400 mg/day) were included. Blood samples were collected at 0.5-4 hours (peak samples group, n = 47) and at 22-24 hours (trough samples group, n = 84) after dose. Fifty-nine ascitic fluid samples were obtained. Single doses of norfloxacin and trimethoprim/sulfamethoxazole were administered to 13 and 5 patients, respectively, (temporal profile group) and samples were collected at 0, 0.5, 1, 1.5, 2, 4, and 24 hours. Norfloxacin, trimethoprim/sulfamethoxazole, cytokines, nitric oxide, expression levels of nuclear factor (NF)-kappaB and inhibitor of NF-kappaB (IkB-alpha), neutrophil oxidative burst, and rate of apoptotic events were determined. RESULTS: All samples were bacterial DNA negative and had no significant levels of lipopolysaccharide. Serum and ascitic levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-12, and nitric oxide were significantly lower in peak than in trough samples. A correlation was present between serum norfloxacins concentrations and tumor necrosis factor-alpha (r = -0.68; P < .001), interferon-gamma (r = -0.66; P < .001), interleukin-12 (r = -0.66; P < .001), and nitric oxide (r = -0.68; P < .001). Serum norfloxacin's highest concentrations (1 +/- 0.5 microg/mL) were achieved at 1-2 hours and concurred in time with the lower levels of cytokines and nitric oxide. Intracellular norfloxacin's highest levels (2 +/- 1 microg/mL/10(7) cells) were observed at 2 hours and concurred with a lower NF-kappaB expression, a reduced anion superoxide generation, and apoptotic rate in response to phorbol myristate acetate. Trimethoprim/sulfamethoxazole did not significantly modulate cytokine expression. CONCLUSIONS: Norfloxacin but not trimethoprim/sulfamethoxazole modulates inflammatory response and directly affects neutrophils in patients with cirrhosis.
Assuntos
Antibacterianos/farmacologia , Citocinas/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Norfloxacino/farmacologia , Explosão Respiratória/efeitos dos fármacos , Idoso , Antibacterianos/uso terapêutico , Infecções Bacterianas/etiologia , Infecções Bacterianas/prevenção & controle , Estudos de Coortes , Estudos Cross-Over , Feminino , Humanos , Cirrose Hepática/terapia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Norfloxacino/uso terapêutico , Peritonite/etiologia , Peritonite/prevenção & controleRESUMO
UNLABELLED: Bacterial infections and severity of associated inflammatory reaction influence prognosis in patients with advanced cirrhosis. We compared the innate immune response to bacterial DNA (bactDNA) translocation with that caused by viable bacteria translocation in patients with spontaneous bacterial peritonitis and the relationship between the cytokine response and serum levels of bactDNA. The bactDNA translocation was investigated in 226 patients with cirrhosis and noninfected ascites, 22 patients with spontaneous bacterial peritonitis, and 10 patients with ascites receiving continuous norfloxacin. Serum and ascitic fluid tumor necrosis factor alpha, interferon-gamma, interleukin-12, and nitric oxide metabolites were measured via enzyme-linked immunosorbent assay. Bacterial genomic identifications were made via amplification and sequencing of the 16S ribosomal RNA gene and digital quantization with DNA Lab-on-chips. The bactDNA was present in 77 noninfected patients (34%) and in all cases of spontaneous bacterial peritonitis, even in those with culture-negative ascitic fluid. No patient receiving norfloxacin showed bactDNA translocation. Levels of all cytokines were similar in patients with bactDNA translocation or spontaneous bacterial peritonitis and significantly higher than in patients without bactDNA or in those receiving norfloxacin. Serum bactDNA concentration paralleled levels of all cytokines and nitric oxide in a series of patients with bactDNA translocation or spontaneous bacterial peritonitis followed during 72 hours. Antibiotic treatment in the series of patients with spontaneous bacterial peritonitis did not abrogate bactDNA translocation in the short term. CONCLUSION: bactDNA translocation-associated cytokine response is indistinguishable from that in patients with spontaneous bacterial peritonitis and is dependent on bactDNA concentration. Norfloxacin abrogates bactDNA translocation and cytokine response.
Assuntos
Ascite/complicações , Infecções Bacterianas/imunologia , DNA Bacteriano/imunologia , Cirrose Hepática/complicações , Peritonite/imunologia , Peritonite/microbiologia , Adulto , Idoso , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ascite/imunologia , DNA Bacteriano/antagonistas & inibidores , DNA Bacteriano/metabolismo , Feminino , Humanos , Imunidade Inata , Interferon gama/análise , Interferon gama/sangue , Interleucina-12/análise , Interleucina-12/sangue , Cirrose Hepática/imunologia , Masculino , Pessoa de Meia-Idade , Norfloxacino/farmacologia , Norfloxacino/uso terapêutico , Peritonite/prevenção & controle , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangueRESUMO
UNLABELLED: We tested the hypothesis that the presence of bacterial DNA (bactDNA) in ascitic fluid and serum is associated with decreased survival in patients with cirrhosis. In a prospective, multicenter study, we analyzed the clinical evolution of 156 patients with cirrhosis and ascites (first or recurrence) with lower than 250 polymorphonuclear cells (PMN)/muL, negative ascites bacteriological culture, and absence of other bacterial infections being admitted for evaluation of large-volume paracentesis, according to the presence of bactDNA at admission. Survival, causes of death, and successive hospital admissions were determined during a 12-month follow-up period. BactDNA was detected in 48 patients. The most prevalent identified bactDNA corresponded to Escherichia coli (n = 32/48 patients, 66.6%). Patients were followed for 12 months after inclusion and in this period 34 patients died: 16 of 108 (15%) bactDNA negative versus 18 of 48 (38%) bactDNA positive (P = 0.003). The most frequent cause of death was acute-on-chronic liver failure in both groups (7/16 and 9/18 in patients without or with bactDNA, respectively), although more prevalent in the first month of follow-up in patients with presence of bactDNA (0 versus 4/7). When considering patients with model for end-stage liver disease (MELD) score less than 15, mortality was significantly higher in those with presence of bactDNA. Spontaneous bacterial peritonitis developed similarly in patients with or without bactDNA at admission. CONCLUSION: The presence of bactDNA in a patient with cirrhosis during an ascitic episode is an indicator of poor prognosis. This fact may be related to the development of acute-on-chronic liver failure at short term and does not predict the development of spontaneous bacterial peritonitis.
Assuntos
Líquido Ascítico/microbiologia , DNA Bacteriano/sangue , Cirrose Hepática/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ascite/epidemiologia , Ascite/microbiologia , Escherichia coli/genética , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Cirrose Hepática/metabolismo , Cirrose Hepática/mortalidade , Falência Hepática/epidemiologia , Falência Hepática/microbiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutrófilos/microbiologia , Peritonite/epidemiologia , Peritonite/microbiologia , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
The cholinergic system is involved in specific behavioural responses and cognitive processes. Here, we examined potential alterations in the brain levels of key cholinergic enzymes in cirrhotic patients and animal models with liver failure. An increase (~30%) in the activity of the acetylcholine-hydrolyzing enzyme, acetylcholinesterase (AChE) is observed in the brain cortex from patients deceased from hepatic coma, while the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase, remains unaffected. In agreement with the human data, AChE activity in brain cortical extracts of bile duct ligated (BDL) rats was increased (~20%) compared to controls. A hyperammonemic diet did not result in any further increase of AChE levels in the BDL model, and no change was observed in hyperammonemic diet rats without liver disease. Portacaval shunted rats which display increased levels of cerebral ammonia did not show any brain cholinergic abnormalities, confirming that high ammonia levels do not play a role in brain AChE changes. A selective increase of tetrameric AChE, the major AChE species involved in hydrolysis of acetylcholine in the brain, was detected in both cirrhotic humans and BDL rats. Histological examination of BDL and non-ligated rat brains shows that the subcellular localization of both AChE and choline acetyltransferase, and thus the accessibility to their substrates, appears unaltered by the pathological condition. The BDL-induced increase in AChE activity was not parallelled by an increase in mRNA levels. Increased AChE in BDL cirrhotic rats leads to a pronounced decrease (~50-60%) in the levels of acetylcholine. Finally, we demonstrate that the AChE inhibitor rivastigmine is able to improve memory deficits in BDL rats. One week treatment with rivastigmine (0.6 mg/kg; once a day, orally, for a week) resulted in a 25% of inhibition in the enzymatic activity of AChE with no change in protein composition, as assessed by sucrose density gradient fractionation and western blotting analysis. In conclusion, this study is the first direct evidence of a cholinergic imbalance in the brain as a consequence of liver failure and points to the possible role of the cholinergic system in the pathogenesis of hepatic encephalopathy.
Assuntos
Acetilcolinesterase/metabolismo , Córtex Cerebral/enzimologia , Encefalopatia Hepática/enzimologia , Acetilcolina/metabolismo , Acetilcolinesterase/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/patologia , Colina O-Acetiltransferase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/psicologia , Humanos , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/patologia , Cirrose Hepática Experimental/psicologia , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Fenilcarbamatos/uso terapêutico , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , RivastigminaRESUMO
BACKGROUND/AIM: The number of patients receiving amiodarone will increase in future years. As clinically significant hepatotoxicity associated with oral amiodarone is infrequent and difficult to predict, a new Bayesian-developed model is proposed to help in the causality assessment of amiodarone-induced liver injury. METHODS: Incidence of abnormal liver enzymes in patients receiving amiodarone was obtained from placebo controlled clinical trials. Published case reports of amiodarone-induced hepatotoxicity were identified through a literature search. Maximum number of expected hepatotoxicity cases in amiodarone and placebo-treated patients was calculated using Poisson distribution. The calculated odds ratio was used as a Prior Odds (PrO) to subsequent quantification, using a Bayesian-approach, of individual amiodarone-induced hepatotoxicity likelihood. RESULTS: PrO of amiodarone-induced hepatotoxicity was 0.48. Thirty nine amiodarone-associated hepatotoxicity case reports were retrieved. Half of published case reports developed an irreversible damage. The amiodarone Bayesian model combining information about latency period and period of remission, together with analytical parameters properly defines the toxicity profile shown in published case reports. The analytical pattern defined by this model is different from the one expected if liver injury in published cases was caused by other etiologies. CONCLUSIONS: A method based on a Bayesian-approach, which links information from clinical trials with clinical hepatotoxicity profile from published case reports can be a useful tool for amiodarone-induced liver injury causality assessment. At present, this method is limited due to scarcity and quality of available data. Further efforts are needed to improve model ability in order to identify amiodarone-induced liver injury.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Teorema de Bayes , Doença Hepática Induzida por Substâncias e Drogas , Modelos Biológicos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Ensaios Enzimáticos Clínicos , Esquema de Medicação , Feminino , Humanos , Hepatopatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Distribuição de Poisson , Reprodutibilidade dos Testes , Medição de Risco , Fatores de RiscoRESUMO
Reelin is an extracellular matrix protein secreted by a variety of cell types in both embryonic and adult tissues, including the liver. However, the physiological significance of Reelin in normal and cirrhotic liver has thus far not been elucidated. We have investigated Reelin levels in the liver and plasma of bile duct ligated (BDL) rats. We observe a 115% increase in full-length Reelin and its 310- and 180-kDa fragments in liver extracts from BDL rats, compared to sham-operated controls (p = 0.005). The overall increase in protein levels was associated with a 30% increase of Reelin transcripts (p = 0.03). Immunohistochemical analysis demonstrated that hepatic stellate cells are the major source of Reelin in the injured liver. Increased liver Reelin in BDL rats leads to a pronounced 165% increase in the plasma levels (p < 0.001), particularly in the less abundant 180-kDa fragment (300% increase; p < 0.001). The data provides evidence that a fraction of plasma Reelin is synthesized in the liver. In human subjects suffering liver cirrhosis the level of the 180-kDa fragment was also increased by 140% in the plasma (p < 0.001). Analysis of Reelin glycosylation by lectin binding demonstrated that the 180- and predominant 310-kDa Reelin fragments in the plasma of cirrhotic patients are differentially glycosylated compared to non-diseased control subjects. The data show that Reelin is up-regulated in experimental liver cirrhosis and that its levels and glycosylation are altered in plasma from patients with cirrhosis, thereby supporting that Reelin is involved in the pathogenesis of liver disease.
Assuntos
Moléculas de Adesão Celular Neuronais/sangue , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/metabolismo , Cirrose Hepática/sangue , Fígado/metabolismo , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/sangue , Serina Endopeptidases/metabolismo , Animais , Ductos Biliares/cirurgia , Western Blotting , Feminino , Glicosilação , Humanos , Imuno-Histoquímica , Ligadura , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteína ReelinaRESUMO
BACKGROUND AND AIMS: Acute pancreatitis (AP) is a systemic inflammatory disease. It is already known that obesity and central fat distribution are related to the severity of AP, but the intimate mechanism of this relationship remains unknown. Obesity and central fat distribution are associated with an inflammatory state that could amplify the systemic inflammatory response (SIR) in AP. The aim of this study was to investigate how obesity and body fat distribution correlate with the SIR and severity of AP. METHODS: 85 consecutive patients with AP were studied. Body mass index, body fat distribution and previous comorbidity were obtained at admission. The SIR was assessed by the serum levels of interleukin (IL)-1beta, IL-1ra, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein. Serum concentrations of the previously mentioned cytokines were also determined in a control group of 40 healthy volunteers. RESULTS: 63 patients (74%) had mild AP and 22 patients (26%) had severe AP. All the cytokines except IL-12p70 and TNF-alpha were increased in the AP group in comparison with the control group. The SIR was significantly increased in patients with severe AP. Obese patients and patients with central fat distribution had significantly more comorbidity, a higher proportion of severe AP and more intense SIR. Patients with comorbidity had a significantly higher proportion of severe AP and more SIR. CONCLUSION: The severity of AP in obese patients and in patients with central fat distribution seems to be related to the comorbidity and the amplification of SIR. and IAP.
Assuntos
Tecido Adiposo/patologia , Mediadores da Inflamação/metabolismo , Obesidade/complicações , Obesidade/patologia , Pancreatite/complicações , Pancreatite/patologia , Doença Aguda , Idoso , Composição Corporal , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Comorbidade , Feminino , Humanos , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND/AIMS: Surveillance programmes (SPs) for hepatocellular carcinoma (HCC) in patients with cirrhosis intend to diagnose the tumour in its early stages when an effective therapy can be applied. The aims of this study have been to compare the survival of patients with HCC being diagnosed or not in SPs, and to establish a more accurate profile of the best target population. METHODS: From January 1996 to June 2005, 290 patients with HCC were included. The relationship between being diagnosed or not in an SP and survival has been analysed in a univariate analysis. Pretreatment variables found to be significant predictors of survival in univariate analysis were included in a multivariate analysis. RESULTS: The mean survival for patients diagnosed in SPs (27 months, 16.6-37.4) was significantly longer than in patients being diagnosed out of these programmes (6 months, 2.6-9.4) (P=0.001). Child-Pugh class A [beta 1.4, 95% confidence interval (CI) 1.14-1.78; P=0.0002] and being diagnosed in SPs (beta 0.4, 95% CI 0.3-0.6; P=0.0003) became the only independent predictive factors of longer survival. CONCLUSIONS: SPs for HCC allow the detection of small tumours and the application of intention-to-cure therapies, which improves survival. However, these programmes do not improve prognosis in patients with advanced cirrhosis.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Vigilância da População , Idoso , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de SobrevidaAssuntos
Hidratação/métodos , Soluções Isotônicas/administração & dosagem , Pancreatite Necrosante Aguda/complicações , Pancreatite Necrosante Aguda/patologia , Pancreatite Necrosante Aguda/terapia , Cloreto de Sódio/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Feminino , Humanos , MasculinoRESUMO
Although acute pancreatitis (AP) may be the consequence of numerous etiologic factors, more than 80% of the episodes are of biliary or alcoholic origin. Although the clinical picture is similar irrespective of the etiology, patients with severe episodes of acute pancreatitis require specific therapeutic maneuvers when biliary-induced while, in the case of alcoholic origin, they only need general support. As a consequence, the early estimation of the etiology is of particular interest, and older age and female sex are frequent characteristics of AP of biliary origin. Together with these factors, abnormal liver function tests have been classically used to identify biliary etiology. Their intrinsic value has grown in the era of new imaging techniques. From another perspective, the plasmatic level of carbohydrate-deficient transferrin seems to be the most accurate technique in differentiating cases of alcohol-induced acute pancreatitis from other etiologies.
Assuntos
Alcoolismo/complicações , Alcoolismo/diagnóstico , Doenças Biliares/complicações , Doenças Biliares/diagnóstico , Pancreatite/etiologia , Doença Aguda , Diagnóstico Diferencial , HumanosRESUMO
CONTEXT: Complete agenesis of the dorsal pancreas is an unusual congenital anomaly. Nowadays, the diagnosis is based on four imaging studies: transabdominal ultrasonography, computed tomography, magnetic resonance cholangiopancreatography and, the gold-standard, endoscopic retrograde cholangiopancreatography. Sometimes the ability of these studies are limited to distinguishing agenesis of the dorsal pancreas from other congenital abnormalities. Endoscopic ultrasound is a minimally invasive technique which permits us to obtain high resolution images of the pancreatic parenchyma and ductal system. CASE REPORT: We report the case of a 23-year-old woman with recurrent episodes of acute pancreatitis and non-conclusive classic imaging studies. Complete agenesis of the dorsal pancreas was demonstrated by endoscopic ultrasound. CONCLUSION: Endoscopic ultrasound may be useful in the diagnosis of agenesis of the dorsal pancreas.
Assuntos
Anormalidades Congênitas/diagnóstico por imagem , Endossonografia/métodos , Pâncreas/anormalidades , Doença Aguda , Adulto , Colangiopancreatografia Retrógrada Endoscópica , Colangiopancreatografia por Ressonância Magnética , Feminino , Humanos , Pâncreas/diagnóstico por imagem , Pancreatite/etiologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The detection of bacterial DNA in serum and ascitic fluid from patients with cirrhosis and ascites is interpreted as molecular evidence of intestinal bacterial translocation and considered sufficient to activate the cellular immune response. In vitro studies on ascitic fluid culture have shown a close relationship between the synthesis of several cytokines and nitric oxide and the presence of bacterial DNA. Since different cell types give rise to cytokines, flow cytometry becomes a powerful tool to discriminate between populations involved in a bacterial challenge. OBJECTIVE: To study the pre-activation status of macrophage/monocyte population ex vivo according to the presence of bacterial DNA. PATIENTS: Patients with cirrhosis and culture-negative, non-neutrocytic ascites, with or without the presence of bacterial DNA in blood and ascitic fluid were studied. METHODS: Flow cytometry analysis of intracellular cytokine expression in monocyte/macrophages from ascitic fluid was performed in basal conditions and after 12 h of cell stimulation adding lypopolysaccharide. RESULTS: Monocyte/macrophages from patients with bacterial DNA showed a significantly higher production of interleukin-6 and tumor necrosis factor alpha in basal conditions than that in cells from patients without the presence of bacterial DNA. The addition of lipopolysaccharide produced a non-significant increment in the expression of these cytokines in patients with the presence of bacterial DNA, while this increment became significant in the other group of patients. CONCLUSIONS: Bacterial translocation in patients with cirrhosis and ascites increases the basal intracellular cytokine expression, reducing its functional reserve capability.