RESUMO
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)µg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF.
Assuntos
Insuficiência Hepática Crônica Agudizada , Injúria Renal Aguda , Biomarcadores , Humanos , Lipocalina-2 , Cirrose Hepática , PrognósticoRESUMO
BACKGROUND: We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. AIM: To characterise phenotype presentation, outcome and severity of AAS DILI. METHODS: Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. RESULTS: AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001-2009 to 8% in 2010-2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035-1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. CONCLUSIONS: Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.
Assuntos
Anabolizantes/efeitos adversos , Androgênios/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Injúria Renal Aguda/etiologia , Adulto , Idoso , Bilirrubina/sangue , Colestase/complicações , Creatinina/sangue , Humanos , Icterícia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Adulto JovemRESUMO
The outcome of patients with cirrhosis and chronic kidney disease treated with combined liver-kidney transplantation (CLKT) is not well known because most series of patients treated with CLKT include not only patients with cirrhosis but also patients with inherited diseases without cirrhosis. To evaluate to what extent the combined kidney transplantation impairs posttransplantation outcome compared to liver transplantation (LT) alone, the outcome of patients with cirrhosis and chronic kidney disease treated with CLKT (n = 20) was compared to that of a group of patients with cirrhosis without chronic kidney disease treated with LT alone matched by age, sex, year of transplantation and severity of cirrhosis (n = 60). The primary end point of the study was survival, and secondary end points were outcome of renal function and complications within 6 months of transplantation. Patients with CLKT had a higher incidence of bacterial infections and transfusion requirements compared to LT patients. The incidence of acute renal failure during the first 6 months was similar, yet the severity of renal failure was greater in patients with CLKT. Hospital and intensive care unit (ICU) stays were longer in the CLKT group. One- and three-year survival probabilities in patients treated with CLKT were 80 and 75% compared to 97 and 88%, respectively, in patients treated with LT. In conclusion, CLKT for patients with cirrhosis and chronic kidney disease is associated with a relatively high frequency of postoperative complications that moderately impairs short-term survival. However, 3-year survival of patients with cirrhosis treated with CLKT is excellent.
Assuntos
Sobrevivência de Enxerto/fisiologia , Nefropatias/cirurgia , Transplante de Rim/fisiologia , Cirrose Hepática/cirurgia , Transplante de Fígado/fisiologia , Adulto , Doença Crônica , Feminino , Humanos , Nefropatias/mortalidade , Transplante de Rim/mortalidade , Cirrose Hepática/mortalidade , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Prevalência , Insuficiência Renal/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: There is little information on the effects of vaptans in patients with cirrhosis. AIM: To investigate the short-term effects of satavaptan, a selective vasopressin V2 receptor antagonist on ascites in cirrhosis without hyponatraemia. METHODS: A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double-blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20-25 mg/day. RESULTS: Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was -0.36 kg (+/-3.03) for placebo vs. -2.46 kg (+/-3.11), -2.08 kg (+/-4.17) and -2.28 kg (+/-3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. CONCLUSIONS: The administration satavaptan for a 14-day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Ascite/tratamento farmacológico , Diuréticos/administração & dosagem , Furosemida/administração & dosagem , Morfolinas/administração & dosagem , Compostos de Espiro/administração & dosagem , Espironolactona/administração & dosagem , Idoso , Peso Corporal/efeitos dos fármacos , Diuréticos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Furosemida/efeitos adversos , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Estudos Prospectivos , Compostos de Espiro/efeitos adversos , Espironolactona/efeitos adversos , Resultado do TratamentoRESUMO
A great variety of autoimmune side effects have been reported during interferon alpha therapy. The presence of anticardiolipin antibodies during interferon alpha therapy in chronic hepatitis C has also been reported. There are no reports on the occurrence of antiphospholipid syndrome in patients with chronic hepatitis C while on pegylated interferon alpha therapy. We report a case of a 46-year-old man who developed antiphospholipid syndrome 12 weeks after starting pegylated interferon alpha plus ribavirin for chronic hepatitis C. The clinical presentation of antiphospholipid syndrome was primary adrenal insufficiency secondary to bilateral adrenal haematoma and subclavian vein thrombosis. A pathogenic role of pegylated interferon alpha as a trigger factor for antiphospholipid syndrome development is suggested.
Assuntos
Síndrome Antifosfolipídica/induzido quimicamente , Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/imunologia , Antivirais/imunologia , Humanos , Interferon alfa-2 , Interferon-alfa/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Trombose Venosa/etiologia , Trombose Venosa/imunologiaRESUMO
Donors after cardiac death (DCD) suffer irreversible cardiac arrest prior to donation. We describe our liver transplant experience with DCD whose cardiac arrest is unexpected, not following the removal of ventilatory support, whom we maintain with normothermic extracorporeal membrane oxygenation (NECMO). A potential donor goes into cardiac arrest outside the hospital and is brought to the hospital under continuous cardiopulmonary resuscitation (CPR). The donor is declared dead and placed on a cardiocompressor. Femoral vessels are cannulated and connected to cardiopulmonary bypass (CPB) to establish NECMO. Blood parameters and CPB pump flow are monitored throughout NECMO, which is continued until cold preservation. From April 2002 to May 2006, 10 of 40 potential DCD livers were transplanted. Only one graft was lost to primary nonfunction (PNF) and another to hepatic artery thrombosis. Posttransplant hepatic function was good. Certain parameters, such as CPR and NECMO times, hepatic transaminases during NECMO, and donor age, determined the viability of DCD liver grafts and were used to establish criteria for their acceptance. Though considered marginal, unexpected DCD can represent an important source of viable livers for transplant if strict acceptance criteria are employed and they are maintained with NECMO prior to recovery.
Assuntos
Morte Súbita Cardíaca , Transplante de Fígado/métodos , Preservação de Órgãos/métodos , Doadores de Tecidos , Biomarcadores/sangue , Reanimação Cardiopulmonar , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Consentimento Livre e Esclarecido , Transplante de Fígado/fisiologia , Seleção de PacientesAssuntos
Ascite/cirurgia , Síndrome Hepatorrenal/terapia , Hiponatremia/terapia , Cirrose Hepática/tratamento farmacológico , Ascite/diagnóstico , Ascite/etiologia , Ensaios Clínicos como Assunto , Consenso , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/etiologia , Humanos , Hiponatremia/diagnóstico , Hiponatremia/etiologia , Cirrose Hepática/complicações , Testes de Função Hepática , Paracentese/métodos , Guias de Prática Clínica como Assunto , EspanhaRESUMO
Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis characterized not only by renal failure but also by marked alterations in systemic haemodynamics and activity of endogenous vasoactive systems. Renal failure is due to a severe vasoconstriction of the renal circulation. The pathogenesis of HRS is not completely understood but it is probably the result of extreme underfilling of the arterial circulation secondary to arterial vasodilation located in the splanchnic circulation. As well as the renal circulation, all other extrasplanchnic vascular beds appear to be vasoconstricted. The diagnosis of HRS is currently based on the exclusion of nonfunctional causes of renal failure; prognosis of patients with HRS is very poor. Liver transplantation is the best option in selected patients, but it is not always applicable as survival expectancy is short. Vasoconstrictor drugs with preferential effect on the splanchnic circulation (vasopressin analogues with a predominant V1 receptor effect, such as terlipressin--Glypressin) are very effective in improving renal function, with reversal of HRS being achieved in approximately two-thirds of patients. There is no agreement as to the terlipressin treatment regimen that is associated with a greater efficacy and lower incidence of side-effects. It appears that the administration of albumin together with terlipressin improves the therapeutic response rate. The impact of treatment on the natural course of HRS remains to be assessed in prospective investigations, but it seems that the reversal of HRS is associated with improved survival. Finally, treatment of patients with HRS with terlipressin before transplantation seems to improve post-transplantation outcome.
Assuntos
Agonistas alfa-Adrenérgicos/uso terapêutico , Síndrome Hepatorrenal/tratamento farmacológico , Lipressina/análogos & derivados , Lipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Síndrome Hepatorrenal/diagnóstico , Humanos , TerlipressinaAssuntos
Ascite/terapia , Diuréticos/uso terapêutico , Síndrome Hepatorrenal/terapia , Hiponatremia/etiologia , Cirrose Hepática/complicações , Vasoconstritores/uso terapêutico , Vasodilatação , Antagonistas dos Receptores de Hormônios Antidiuréticos , Ascite/etiologia , Edema/etiologia , Síndrome Hepatorrenal/tratamento farmacológico , Síndrome Hepatorrenal/fisiopatologia , Humanos , Hiponatremia/fisiopatologia , Hiponatremia/terapia , Rim/fisiopatologia , Cirrose Hepática/fisiopatologia , Transplante de Fígado , Derivação Portossistêmica Cirúrgica , Diálise Renal , Vasodilatação/efeitos dos fármacosRESUMO
Renal function abnormalities and ascites in cirrhosis are the final consequence of a circulatory dysfunction characterized by marked splanchnic arterial vasodilation. This causes a reduction in effective arterial blood volume and the homoeostatic activation of vasoconstrictor and sodium-retaining systems. Albumin is very effective in preventing renal failure associated with large-volume paracentesis and spontaneous bacterial peritonitis, conditions that are known to cause an impairment of circulatory function in patients with cirrhosis and ascites. Moreover, albumin administration improves survival in patients with spontaneous bacterial peritonitis. In patients with hepatorenal syndrome the administration of vasoconstrictor drugs in combination with albumin improves circulatory and renal function markedly and survival slightly. By contrast, the administration of albumin without vasoconstrictors has marginal or no effects on renal function in this setting.
Assuntos
Cirrose Hepática/terapia , Substitutos do Plasma/uso terapêutico , Albumina Sérica/uso terapêutico , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/terapia , Humanos , Paracentese , Insuficiência Renal/prevenção & controleAssuntos
Síndrome Hepatorrenal/tratamento farmacológico , Vasoconstritores/uso terapêutico , Agonistas alfa-Adrenérgicos/uso terapêutico , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Avaliação de Medicamentos , Quimioterapia Combinada , Síndrome Hepatorrenal/classificação , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/etiologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Lipressina/análogos & derivados , Lipressina/uso terapêutico , Midodrina/administração & dosagem , Midodrina/uso terapêutico , Octreotida/uso terapêutico , Ornipressina/uso terapêutico , Projetos Piloto , Circulação Renal/efeitos dos fármacos , TerlipressinaRESUMO
BACKGROUND/AIMS: High-conductance Ca(2+)-activated K(+) (BK(Ca)) channels modulate the effects of vasoactive factors in contractile cells. It is unknown whether hepatic stellate cells (HSCs) contain BK(Ca) channels and what their role in the regulation of HSCs contractility is. METHODS: The presence of BK(Ca) channels in HSCs was assessed by the patch-clamp technique. The functional role of BK(Ca) channels was investigated by measuring intracellular calcium concentration ([Ca(2+)](i)) and cell contraction in individual cells after stimulation with endothelin-1 in the presence or absence of specific modulators of BK(Ca) channels. RESULTS: BK(Ca) channels were detected by patch-clamp in most of the activated HSCs studied. Incubation of cells with iberiotoxin, a BK(Ca) channel blocker, increased both the sustained phase of [Ca(2+)](i) elicited by endothelin-1 and the number of cells undergoing contraction, while the use of NS1619, a BK(Ca) channel opener, induced opposite effects. Stimulation of HSCs with S-nitroso-N-acetyl-penicillamine (SNAP), a nitric oxide (NO)-donor, increased the opening of BK(Ca) channels and reduced the effects of endothelin-1. Conversely, iberiotoxin abolished the inhibitory effect of SNAP on endothelin-induced [Ca(2+)](i) increase and cell contraction. CONCLUSIONS: Activated human HSCs contain BK(Ca) channels that modulate the contractile effect of endothelin-1 and mediate the inhibitory action of NO.
Assuntos
Endotelina-1/farmacologia , Fibroblastos/metabolismo , Fígado/metabolismo , Músculo Liso/metabolismo , Óxido Nítrico/fisiologia , Canais de Potássio Cálcio-Ativados/fisiologia , Benzimidazóis/farmacologia , Cálcio/metabolismo , Células Cultivadas , Fibroblastos/fisiologia , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta , Fígado/citologia , Músculo Liso/citologia , Músculo Liso/fisiologia , Doadores de Óxido Nítrico/farmacologia , Técnicas de Patch-Clamp , Peptídeos/farmacologia , Canais de Potássio Cálcio-Ativados/agonistas , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , S-Nitroso-N-Acetilpenicilamina/farmacologiaRESUMO
To assess the incidence, clinical course, predictive factors, and prognosis of renal failure in patients with cirrhosis and gastrointestinal bleeding, 175 consecutive episodes of gastrointestinal bleeding in 161 patients were analyzed. Renal failure occurred in 20 (11%) episodes and was transient in 8 episodes and nontransient in 12. Renal failure was more common in patients with cirrhosis than in a control population of bleeding patients without cirrhosis matched by age and severity of the bleeding episode. Among 39 clinical and laboratory variables obtained at admission or during hospitalization related with the bleeding episode or with liver and renal function, the presence of hypovolemic shock, number of packed red blood cells transfused, Child-Pugh class at admission, and baseline platelet count were independent predictors of renal failure. The development of renal failure and hypovolemic shock was the only independent predictors of in-hospital mortality. Mortality rate among the 20 episodes with renal failure was 55% (11 deaths) as compared with only 3% (5 deaths) in the 155 episodes without renal failure (P <.01). The development of nontransient renal failure entailed a much greater mortality as compared with transient renal failure (10 of 12 [83%] vs. 1 of 8 [12%]; P <.01). In conclusion, renal failure is a common event in patients with cirrhosis and gastrointestinal bleeding, the occurrence of which is mainly related to the severity of bleeding and baseline liver function. Renal failure is a strong predictor of mortality in patients with cirrhosis and gastrointestinal bleeding.
Assuntos
Hemorragia Gastrointestinal/complicações , Cirrose Hepática/complicações , Insuficiência Renal/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal/epidemiologia , Insuficiência Renal/mortalidadeRESUMO
We report 2 patients with Budd-Chiari (BC) syndrome secondary to thrombogenic conditions who underwent transjugular intrahepatic portosystemic shunt (TIPS) placement because of refractory ascites and impending liver failure. After TIPS placement, there was marked symptomatic relief and improvement in liver function, but the courses of both patients were complicated by the development of an inferior vena cava (IVC) syndrome caused by segmental stenosis of the suprahepatic IVC just at the outflow jet of the TIPS at 11 and 9 months later. One patient underwent liver transplantation, and the other patient, caval angioplasty and stenting. Stenosis of the IVC represents an unrecognized complication of TIPS in patients with BC syndrome.
Assuntos
Síndrome de Budd-Chiari/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Veia Cava Inferior/patologia , Adulto , Angioplastia , Constrição Patológica , Feminino , Humanos , Transplante de Fígado , Masculino , StentsRESUMO
BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedullin (ADM), a peptide produced by most contractile cells. METHODS AND RESULTS: Stimulation of HSCs with ADM resulted in a dose-dependent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca2+]i and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method. The existence of the receptor CRLR for ADM and their associated proteins RAMP-1 and RAMP-2 was demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, activated human HSCs spontaneously secreted ADM in the culture medium in a time-dependent manner. ADM secretion was markedly enhanced by tumour necrosis factor-alpha and interleukin-1beta. Specific mRNA for ADM (RT-PCR and Northern blot) was detected in HSCs and increased after incubation of cells with cytokines. CONCLUSIONS: Human HSCs have functional receptors for ADM, the stimulation of which blunts the contractile effect of endothelin-1. Cultured human HSCs secrete ADM in baseline conditions. This secretion is markedly increased by cytokines. These results suggest that ADM can regulate HSCs' contractility in an autocrine manner.
Assuntos
Fígado/citologia , Fígado/metabolismo , Peptídeos/metabolismo , Adrenomedulina , Proteína Semelhante a Receptor de Calcitonina , Sinalização do Cálcio/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , AMP Cíclico/metabolismo , Endotelina-1/farmacologia , Humanos , Interleucina-1/farmacologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Peptídeos/farmacologia , Receptores de Adrenomedulina , Receptores da Calcitonina/metabolismo , Receptores de Peptídeos/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells, which develop contractile properties and contribute to increased resistance to blood flow. We investigated whether this phenotypic activation includes changes in the expression of L-type voltage-operated Ca2+ channels (VOCC), which mediate Ca2+ influx and regulate cell contraction in vascular cell types. Rat HSCs were studied in the quiescent phenotype and after their activation in vitro (cultured on plastic for 14 days) and in vivo (isolated from rats with CCl(4)-induced cirrhosis). Patch-clamp studies showed Ca2+ currents through L-type VOCC in HSCs activated both in vitro and in vivo, whereas no currents were detected in quiescent HSCs. Moreover, binding studies with (3)H-isradipine, a specific L-type VOCC antagonist, showed a large number of binding sites in activated HSCs, while no specific binding was found in quiescent HSCs. Finally, messenger RNA (mRNA) encoding L-type VOCC was not detected in quiescent HSCs as assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, whereas it was present in activated HSCs. Stimulation of L-type VOCC with KCl resulted in a marked increase in [Ca2+](i) followed by cell contraction in HSCs activated both in vitro and in vivo, whereas no effects were observed in quiescent HSCs. We conclude that the activation of HSCs is associated with up-regulation of L-type VOCC that mediate Ca2+ influx and cell contraction. These results may be relevant to the pathogenesis of portal hypertension.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Fígado/fisiologia , Animais , Northern Blotting , Bloqueadores dos Canais de Cálcio/metabolismo , Eletrofisiologia , Isradipino/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Técnicas de Patch-Clamp , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Patients with cirrhosis have significant abnormalities in their fluid and electrolyte balance, this is manifested mainly by the development of ascites and edema. Ascites is the most common complication of patients with cirrhosis and its development constitutes the first and most important manifestation of the disease. Patients with advanced cirrhosis and portal hypertension often show an abnormal extracellular fluid volume regulation, which results in accumulation of fluid as ascites, pleural effusion, or edema. This abnormality in volume regulation is associated with significant changes in the splanchnic circulation and renal circulation that induce sodium and water retention. During the last decade significant advances have been accomplished in regard to the pathogenesis and the treatment ascites. The description of a new hypothesis, the identification of new vasoactive factors involved in the pathogenesis of arterial vasodilation and the introduction of different therapeutic modalities such as therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, aquaretics agents, and liver transplantation are all proof of this. Likewise, the description of predictive factors for the survival of patients with cirrhosis has been of major importance for the identification of patients candidates for liver transplantation.
Assuntos
Ascite/fisiopatologia , Ascite/terapia , Hiponatremia/fisiopatologia , Hiponatremia/terapia , Cirrose Hepática/fisiopatologia , Ascite/complicações , Humanos , Hiponatremia/complicações , Cirrose Hepática/complicaçõesRESUMO
BACKGROUND/AIMS: Parameters evaluating renal function and systemic hemodynamics are of prognostic significance in cirrhosis with ascites but are rarely used in the evaluation of survival of these patients. The aim of the current study was to develop a prognostic model to estimate survival of patients with cirrhosis and ascites. METHODS: 216 Cirrhotic patients admitted to hospital for the treatment of ascites were evaluated. Thirty-two demographic, clinical and laboratory variables, including parameters assessing liver and renal function and systemic hemodynamics, were analyzed as predictive factors of survival by using a Cox regression model. RESULTS: Four variables had independent prognostic value: renal water excretion, as assessed by measuring diuresis after water load, mean arterial pressure, Child-Pugh class, and serum creatinine. According to these features a prognostic index was calculated that allows to estimate survival in patients with cirrhosis and ascites. The model accurately predicted survival in an independent series of 84 patients with cirrhosis and ascites. CONCLUSION: A prognostic model that uses four easily available variables and predicts prognosis in cirrhotic patients with ascites has been developed. This model may be useful in the evaluation of patients with ascites for liver transplantation.
Assuntos
Ascite/mortalidade , Cirrose Hepática/mortalidade , Feminino , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: The leukotrienes C(4)/D(4)/E(4) (cysteinyl-LTs) are 5-lipoxygenase (5-LO)-derived eicosanoids with potent vasoconstrictor, proliferative, and profibrogenic properties that may participate in key pathophysiologic events in liver cirrhosis. We examined the cysteinyl-LT biosynthetic pathway in liver tissue and purified liver cells isolated from rats with carbon tetrachloride-induced cirrhosis, and assessed the vasoactive properties of LTD(4) in hepatic stellate cells (HSCs) and anesthetized rats. METHODS & RESULTS: Liver homogenates from cirrhotic rats had increased 5-LO mRNA and cysteinyl-LT content, as determined by Northern blot and enzyme immunoassay, respectively. In isolated rat liver cells, 5-LO mRNA expression was found to be restricted to Kupffer cells. However, among the liver cells (i.e., hepatocytes, Kupffer cells, HSCs, and sinusoidal endothelial cells), hepatocytes exhibited the highest ability to generate cysteinyl-LTs from the unstable intermediate LTA(4). Hepatocytes from cirrhotic rats showed an enhanced baseline generation of cysteinyl-LTs, but their ability to synthesize cysteinyl-LTs from exogenous LTA(4) was found to be similar to that of hepatocytes from normal animals. Both LTD(4) and hepatocyte-conditioned medium increased intracellular Ca(2+) concentration and induced contraction in HSCs, suggesting that hepatocyte-derived cysteinyl-LTs could act in a paracrine fashion on nearby nonparenchymal liver cells. The relevance of these in vitro findings was further established in vivo by the observation that LTD(4) significantly increased portal pressure in anesthetized rats. CONCLUSIONS: These data suggest a role for hepatocyte-derived cysteinyl-LTs in mediating hepatic vascular tone abnormalities in cirrhosis.