RESUMO
BACKGROUND AND AIMS: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker. APPROACH AND RESULTS: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively. CONCLUSIONS: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making.
Assuntos
Tempo de Circulação Sanguínea/métodos , Circulação Hepática , Falência Hepática Aguda , Fígado , Imagem de Perfusão/métodos , Ultrassonografia Doppler/métodos , Meios de Contraste/farmacologia , Humanos , Aumento da Imagem/métodos , Japão/epidemiologia , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-ß1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-ß1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-ß1 antibody (anti-TGF-ß1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-ß1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-ß1 decrease on blood-brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins' decrease in analyzed fractions occurred in anti-TGF-ß1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-ß mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-ß1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-ß1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.
Assuntos
Azoximetano/efeitos adversos , Encéfalo/fisiopatologia , Encefalopatia Hepática/fisiopatologia , Falência Hepática Aguda/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Anticorpos/administração & dosagem , Anticorpos/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo , Fenômenos Eletrofisiológicos , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/metabolismo , Injeções Intraperitoneais , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/fisiopatologia , Masculino , Camundongos , Ratos , Sinaptofisina/metabolismo , Sinaptotagminas/metabolismoRESUMO
BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.
Assuntos
Causas de Morte , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Terminal/induzido quimicamente , Falência Hepática Aguda/induzido quimicamente , Sistema de Registros , Doença Aguda , Adulto , Distribuição por Idade , Idoso , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , China/epidemiologia , Doença Crônica , Estudos de Coortes , Intervalos de Confiança , Doença Hepática Terminal/epidemiologia , Doença Hepática Terminal/fisiopatologia , Feminino , Humanos , Incidência , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND AND AIM: Massive hepatic necrosis is a rare but often fatal complication of various liver injuries. Nevertheless, some patients can survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes and/or progenitor cells can participate in this process but the mechanism of hepatic recovery is vague. METHODS: We examined 13 explanted human livers removed for acute liver failure. Combined immunohistochemistry, digital image analysis, and three-dimensional reconstruction of serial sections were applied. RESULTS: Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes started to proliferate and arrange into acinar structures and expressed α-fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci often containing complete portal triads were arranged around surviving central veins. Their fusion eventually could be an attempt to re-establish the hepatic lobules. CONCLUSIONS: Regeneration of human livers following massive hepatic necrosis can occur in two ways-either through proliferation of α-fetoprotein-positive acinary-arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Further investigation of these regenerative pathways may help identify biomarkers for likelihood of complete regeneration and hence have therapeutic implications.
Assuntos
Falência Hepática Aguda/fisiopatologia , Regeneração Hepática/fisiologia , Fígado/patologia , Fígado/fisiologia , NecroseRESUMO
Acute liver failure (ALF) is a rare and life-threatening entity in pediatrics which requires a multidis ciplinary approach for early diagnosis and treatment. The objective of this article is to update defi nitions, management, and available treatments. We obtained the articles by reviewing the literature available between 2000 and 2020 in different databases (Pubmed, LILACS, BIREME, Google Scholar, and UpToDate), using terms such as "acute liver failure" in Pubmed, and in other databases "pedia tric acute liver failure" and "falla hepática aguda en pediatría" using filters such as age, publication date, and types of study (clinical trials, review articles, systematic reviews, and case-control studies). We chose those articles with the highest number of citations and with recent data. The ALF requires support in the pediatric intensive care unit and its early diagnosis favors the beginning of treatment. In pediatric patients with ALF, it is recommended to focus on age-specific diagnostic testing. There is no agreement regarding the liver transplantation in pediatric cases of ALF.
Assuntos
Falência Hepática Aguda , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Falência Hepática Aguda/terapia , PediatriaRESUMO
BACKGROUND & AIMS: Severe acute liver injury is a grave complication of exertional heatstroke. Liver transplantation (LT) may be a therapeutic option, but the criteria for LT and the optimal timing of LT have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context. METHODS: This was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related severe acute liver injury with a prothrombin time (PT) of less than 50%. A total of 24 male patients were studied. RESULTS: Fifteen of the 24 patients (median nadir PT: 35% [29.5-40.5]) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5-12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% [9-12]) were withdrawn from the list because of an elevation of PT values that mainly occurred between day 2 and day 3. Ultimately, 4 patients underwent transplantation as their PT persisted at <10%, 3â¯days (2.75-3.25) after the onset of exertional heatstroke, and they had more than 3 organ dysfunctions. Of these 4 patients, 3 were still alive 1â¯year later. Histological analysis of the 4 explanted livers demonstrated massive or sub-massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance. CONCLUSION: The first-line treatment for exertional heatstroke-related severe acute liver injury is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3⯠days following the onset of heatstroke, was the trigger that prompted LT, was the trigger adopted in order to decide upon LT. LAY SUMMARY: Acute liver injury due to heatstroke can progress to acute liver failure with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related acute liver failure. We confirmed thatmedication is the first-line therapy acute liver injury caused by heatstroke, with LT only rarely necessary. A decision to perform LT should not be made hastily. Fluctuations in prothrombin time and the patient's clinical status should be considered even in the event of severe liver failure.
Assuntos
Golpe de Calor , Falência Hepática Aguda , Transplante de Fígado/métodos , Fígado , Tempo de Protrombina/métodos , Adulto , França , Golpe de Calor/complicações , Golpe de Calor/fisiopatologia , Humanos , Fígado/patologia , Fígado/fisiopatologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Falência Hepática Aguda/cirurgia , Masculino , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/terapia , Escores de Disfunção Orgânica , Avaliação de Resultados em Cuidados de Saúde , Seleção de Pacientes , Esforço Físico , Estudos RetrospectivosRESUMO
PURPOSE: To report the results of transjugular intrahepatic portosystemic shunt (TIPS) reductions for hepatic encephalopathy (HE), acute liver failure (ALF), and pulmonary hypertension (PH). MATERIALS AND METHODS: A single-institution retrospective review analysis was performed between 2007 and 2017 on patients undergoing TIPS reduction at single tertiary liver transplant center. A total of 27 patients (14 males and 13 females) underwent TIPS reduction for refractory HE (n = 18), ALF (n = 7), and PH (n = 2). The average age at time of reduction was 59 years (range, 23-73; standard deviation [SD], 8). Mean prereduction Model of End-State Liver Disease-Na and portosystemic pressure gradient were 19 (range, 11-29; SD, 6) and 9.4 mm Hg (range, -2 to 19; SD, 4.8), respectively. Comparison between responders and nonresponders was performed for multiple variables using a 2-tailed t test. Methods of reduction were compared in cases of HE. RESULTS: Technical success, defined as a decrease of at least 50% of the caliber of the shunt, was 100%. Clinical success rates in improving HE, ALF, and PH were calculated at 89%, 71%, and 100%, respectively. Eight patients had major and 10 had minor complications after the reductions. There were 3 shunt thrombosis. Pre- and postreduction Model of End-State Liver Disease-Na, portosystemic pressure gradient change, duration of indwelling TIPS, and reduction method were not significantly different between responders and nonresponders. Six-month survival rates were 80%, 20%, and 100% for HE, ALF, and PH, respectively. CONCLUSIONS: TIPS reduction is effective in reversing refractory HE, ALF, and PH after TIPS creation. TIPS reduction is associated with a high rate of complications and should be reserved for severe refractory overshunting complications.
Assuntos
Angioplastia com Balão , Implante de Prótese Vascular , Encefalopatia Hepática/cirurgia , Hipertensão Pulmonar/cirurgia , Falência Hepática Aguda/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Adulto , Idoso , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Bases de Dados Factuais , Feminino , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Reoperação , Estudos Retrospectivos , Fatores de Risco , Stents , Texas , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Acute liver failure is a rare hepatic emergent situation that affects primarily young people and has often a catastrophic or even fatal outcome. Definition of acute liver failure has not reached a universal consensus and the interval between the appearance of jaundice and hepatic encephalopathy for the establishment of the acute failure is a matter of debate. Among the wide variety of causes, acetaminophen intoxication in western societies and viral hepatitis in the developing countries rank at the top of the etiology list. Identification of the clinical appearance and initial management for the stabilization of the patient are of vital significance. Further advanced therapies, that require intensive care unit, should be offered. The hallmark of treatment for selected patients can be orthotopic liver transplantation. Apart from well-established treatments, novel therapies like hepatocyte or stem cell transplantation, additional new therapeutic strategies targeting acetaminophen intoxication and/or hepatic encephalopathy are mainly experimental, and some of them do not belong, yet, to clinical practice. For clinicians, it is substantial to have the alertness to timely identify the patient and transfer them to a specialized center, where more treatment opportunities are available.
Assuntos
Serviço Hospitalar de Emergência/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Falência Hepática Aguda/terapia , Humanos , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Transplante de Fígado , Seleção de PacientesRESUMO
Research on non-invasive neuromonitoring specific to PALF is limited. This systematic review identifies and synthesis the existing literature on non-invasive approaches to monitoring for neurological sequelae in patients with PALF. A series of literature searches were performed to identify all publications pertaining to five different non-invasive neuromonitoring modalities, in line with PRISMA guidelines. Each modality was selected on the basis of its potential for direct or indirect measurement of cerebral perfusion; studies on electroencephalographic monitoring were therefore not sought. Data were recorded on study design, patient population, comparator groups, and outcomes. A preponderance of observational studies was observed, most with a small sample size. Few incorporated direct comparisons of different modalities; in particular, comparison to invasive intracranial pressure monitoring was largely lacking. The integration of current evidence is considered in the context of the clinically significant distinctions between pediatric and adult ALF, as well as the implications for planning of future investigations to best support the evidence-based clinical care of these patients.
Assuntos
Cuidados Críticos/métodos , Encefalopatia Hepática/diagnóstico , Falência Hepática Aguda/complicações , Monitorização Neurofisiológica/métodos , Criança , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/terapia , Humanos , Falência Hepática Aguda/fisiopatologia , Falência Hepática Aguda/terapiaRESUMO
INTRODUCTION AND OBJECTIVES: The aim of this paper was to evaluate the association of hepatic encephalopathy with survival of patients with liver failure. MATERIALS AND METHODS: We retrieved the relevant articles from the PubMed, Embase and Cochrane Library, up to May 2017. The pooled odds ratio (OR) as well as their 95% confidence intervals (CI) was calculated by the software of R package version 3.12. RESULTS: Total 13 studies with 2071 liver failure patients were included and reanalyzed in this meta-analysis. The results proved the prognostic value of hepatic encephalopathy for survival of patients with liver failure (OR=5.62, 95%CI=6.30-9.82, P<0.001). The subgroup analyses showed that the type of liver failure and the follow up duration may be the factor influencing the association between hepatic encephalopathy and survival of patients with liver failure. CONCLUSIONS: The results proved that hepatic encephalopathy was a prognostic factor of survival in patients with liver failure.
Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Encefalopatia Hepática/epidemiologia , Falência Hepática Aguda/mortalidade , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/fisiopatologia , Hepatite B/complicações , Hepatite Autoimune/complicações , Humanos , Falência Hepática/etiologia , Falência Hepática/mortalidade , Falência Hepática/fisiopatologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Razão de Chances , Prognóstico , Taxa de SobrevidaRESUMO
We have reported that tumor necrosis factor-α (TNF-α) is critical for reduction of glomerular filtration rate (GFR) in rats with fulminant hepatic failure (FHF). The present study aims to evaluate the underlying mechanisms of decreased GFR during acute hepatic failure. Rats with FHF induced by d-galactosamine plus lipopolysaccharide (GalN/LPS) were injected intravenously with recombinant lentivirus harboring short hairpin RNA against the protein kinase C-α ( PKC-α) gene (Lenti-shRNA-PKC-α). GFR, serum levels of aminotransferases, creatinine, urea nitrogen, potassium, sodium, chloride, TNF-α, and endothelin-1 (ET-1), as well as type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) expression in renal tissue were assessed. The effects of PKC-α silencing on TNF-α-induced IP3R1, specificity protein 1 (SP-1), and c-Jun NH2-terminal kinase (JNK) expression, as well as cytosolic calcium content were determined in glomerular mesangial cell (GMCs) with RNAi against PKC-α. Renal IP3R1 overexpression was abrogated by pre-treatment with Lenti-shRNA-PKC-α. The PKC-α silence significantly improved the compromised GFR, reduced Cr levels, and reversed the decrease in glomerular inulin space and the increase in glomerular calcium content in GalN/LPS-exposed rats. TNF-α treatment increased expression of PKC-α, IP3R1, specificity protein 1 (SP-1), JNK, and p-JNK in GMCs and increased Ca2 + release and binding activity of SP-1 to the IP3R1 promoter. These effects were blocked by transfection of siRNA against the PKC-α gene, and the PKC-α gene silence also restored cytosolic Ca2+ concentration. RNAi targeting PKC-α inhibited TNF-α-induced IP3R1 overexpression and in turn improved compromised GFR in the development of acute kidney injury during FHF in rats.
Assuntos
Injúria Renal Aguda/terapia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Taxa de Filtração Glomerular/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Rim/efeitos dos fármacos , Falência Hepática Aguda/terapia , Proteína Quinase C-alfa/metabolismo , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/fisiopatologia , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Modelos Animais de Doenças , Receptores de Inositol 1,4,5-Trifosfato/genética , Rim/enzimologia , Rim/fisiopatologia , Falência Hepática Aguda/enzimologia , Falência Hepática Aguda/fisiopatologia , Masculino , Proteína Quinase C-alfa/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Cerebral blood flow (CBF) is impaired in acute liver failure (ALF), however, the complexity of the underlying mechanisms has often led to inconclusive interpretations. Regulation of CBF depends at least partially on variations in the local brain L-arginine concentration and/or its metabolic rate. In ALF, other factors, like an increased concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and elevated level of L-glutamine, may contribute to CBF alteration. This study demonstrated strong differences in the reactivity of the middle cerebral arteries and their response to extravascular L-arginine application between vessels isolated from rats with thioacetamide (TAA)-induced ALF and control animals. Our results also showed the decrease in the cerebral perfusion in TAA rats measured by arterial spin labeling perfusion magnetic resonance. Subsequently, we aimed to investigate the importance of balance between the concentration of ADMA and L-arginine in the CBF regulation. In vivo, intraperitoneal L-arginine administration in TAA rats corrected: (i) decrease in cerebral perfusion, (ii) decrease in brain extracellular L-arginine/ADMA ratio and (iii) increase in brain L-glutamine concentration. Our study implicates that impaired vascular tone of cerebral arteries is most likely associated with exposure to high ADMA and L-glutamine levels resulting in limited availability of L-arginine and might be responsible for reduced cerebral perfusion observed in ALF.
Assuntos
Arginina/análogos & derivados , Arginina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Glutamina/metabolismo , Falência Hepática Aguda/fisiopatologia , Animais , Arginina/metabolismo , Encéfalo/diagnóstico por imagem , Espaço Extracelular/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , TioacetamidaRESUMO
The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.
Assuntos
Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Criança , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Retículo Endoplasmático/metabolismo , Hepatomegalia/complicações , Hepatomegalia/fisiopatologia , Humanos , Recém-Nascido , Icterícia Neonatal/complicações , Icterícia Neonatal/fisiopatologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/fisiopatologia , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Terminologia como AssuntoRESUMO
BACKGROUND & AIMS: Liver failure results in hyperammonaemia, impaired regulation of cerebral microcirculation, encephalopathy, and death. However, the key mediator that alters cerebral microcirculation remains unidentified. In this study we show that topically applied ammonium significantly increases periarteriolar adenosine tone on the brain surface of healthy rats and is associated with a disturbed microcirculation. METHODS: Cranial windows were prepared in anaesthetized Wistar rats. The flow velocities were measured by speckle contrast imaging and compared before and after 30â¯min of exposure to 10â¯mM ammonium chloride applied on the brain surface. These flow velocities were compared with those for control groups exposed to artificial cerebrospinal fluid or ammonium plus an adenosine receptor antagonist. A flow preservation curve was obtained by analysis of flow responses to a haemorrhagic hypotensive challenge and during stepwise exsanguination. The periarteriolar adenosine concentration was measured with enzymatic biosensors inserted in the cortex. RESULTS: After ammonium exposure the arteriolar flow velocity increased by a median (interquartile range) of 21.7% (23.4%) vs. 7.2% (10.2%) in controls (nâ¯=â¯10 and nâ¯=â¯6, respectively, pâ¯<0.05), and the arteriolar surface area increased. There was a profound rise in the periarteriolar adenosine concentration. During the hypotensive challenge the flow decreased by 27.8% (14.9%) vs. 9.2% (14.9%) in controls (pâ¯<0.05). The lower limit of flow preservation remained unaffected, 27.7 (3.9) mmHg vs. 27.6 (6.4) mmHg, whereas the autoregulatory index increased, 0.29 (0.33) flow units per millimetre of mercury vs. 0.03 (0.21) flow units per millimetre of mercury (pâ¯<0.05). When ammonium exposure was combined with topical application of an adenosine receptor antagonist, the autoregulatory index was normalized. CONCLUSIONS: Vasodilation of the cerebral microcirculation during exposure to ammonium chloride is associated with an increase in the adenosine tone. Application of a specific adenosine receptor antagonist restores the regulation of the microcirculation. This indicates that adenosine could be a key mediator of the brain dysfunction seen during hyperammonaemia and is a potential therapeutic target. LAY SUMMARY: In patients with liver failure, disturbances in brain function are caused in part by ammonium toxicity. In our project we studied how ammonia, through adenosine release, affects the blood flow in the brain of rats. In our experimental model we demonstrated that the detrimental effect of ammonia on blood flow regulation was counteracted by blocking the adenosine receptors in the brain. With this observation we identified a novel potential treatment target. If we can confirm our findings in a future clinical study, this might help patients with liver failure and the severe condition called hepatic encephalopathy.
Assuntos
Adenosina/metabolismo , Cloreto de Amônio/toxicidade , Córtex Cerebral/metabolismo , Circulação Cerebrovascular/fisiologia , Administração Tópica , Cloreto de Amônio/administração & dosagem , Animais , Arteríolas/metabolismo , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Córtex Cerebral/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/fisiopatologia , Humanos , Hiperamonemia/complicações , Hiperamonemia/fisiopatologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/fisiopatologia , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/fisiologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
PURPOSE OF REVIEW: Acute liver failure (ALF) is a severe and complex illness and one of the most daunting conditions managed in the ICU. Because the renal care is intertwined with multiple disciplines, the aim of this review is to examine the multifactorial pathogenesis of cerebral edema in ALF, covering basic established facts as well as recent advances in our understanding of this condition. RECENT FINDINGS: Acetaminophen remains the most common cause of ALF in the United States and many European countries. The incidence of cerebral edema continues to decline owing to earlier detection and improved management. The pathogenesis of cerebral edema has shifted from a unifactorial hypothesis involving the failed liver to a multifactorial cause. Recent evidence focuses on the role of liver-induced systemic inflammation and its implication in increasing the permeability of the blood-brain barrier. The role of brain aquaporin-4 in mediating water entry into the brain is further clarified. Controversial data regarding the effect of acute kidney injury on the brain emerged. Hyponatremia has been shown to worsen the outcome in acute-on-chronic liver failure patients thus validating findings in animal models. New evidence shed the light on the changes in serum osmolality and potential tissue hypoxia during continuous renal replacement therapy and points to the risks associated with such therapy. SUMMARY: ALF is a severe systemic illness that is potentially reversible. Understanding the interaction between the multiple failed organs will help the nephrologist provide well tolerated and efficient care.
Assuntos
Injúria Renal Aguda/fisiopatologia , Edema Encefálico/terapia , Falência Hepática Aguda/fisiopatologia , Nefrologia , Papel do Médico , Água/metabolismo , Injúria Renal Aguda/complicações , Animais , Aquaporina 4/metabolismo , Barreira Hematoencefálica/fisiopatologia , Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Humanos , Hiponatremia/complicações , Hiponatremia/fisiopatologia , Inflamação/fisiopatologia , Falência Hepática Aguda/complicações , PermeabilidadeRESUMO
Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).
Assuntos
Imunidade Adaptativa/fisiologia , Galectinas/metabolismo , Homeostase/imunologia , Hepatopatias/imunologia , Hepatopatias/fisiopatologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/fisiopatologia , Hepatite/imunologia , Hepatite/fisiopatologia , Hepatite Autoimune/imunologia , Hepatite Autoimune/fisiopatologia , Humanos , Imunidade Inata/fisiologia , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/fisiopatologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/fisiopatologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/fisiopatologia , Sensibilidade e EspecificidadeRESUMO
Here we report the case of a 63-year-old female patient who was admitted with acute liver failure. The etiology turned out to be an acute fulminant hepatitis caused by hepatitis C virus (HCV) infection of unknown origin. Fulminant hepatitis due to acute hepatitis C is very rare and hardly reported but a potential cause of acute liver failure due to massive hepatic necrosis, which may lead to encephalitis and multi-organ-failure. During follow-up spontaneous virological clearance was observed. The case illustrates that acute HCV infection, which is confirmed by the detection of HCV-RNA, has to be considered in the differential diagnosis of acute liver failure.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/complicações , Falência Hepática Aguda/virologia , Doença Aguda , Feminino , Hepacivirus/genética , Hepatite C/genética , Humanos , Fígado/patologia , Falência Hepática/etiologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/fisiopatologia , Pessoa de Meia-Idade , RNA Viral/isolamento & purificaçãoRESUMO
Indocyanine green (ICG) is a water-soluble dye that is bound to plasma proteins when administered intravenously and nearly completely eliminated from the blood by the liver. ICG elimination depends on hepatic blood flow, hepatocellular function and biliary excretion. ICG elimination is considered as a useful dynamic test describing liver function and perfusion in the perioperative setting, i.e., in liver surgery and transplantation, as well as in critically ill patients. ICG plasma disappearance rate (ICG-PDR) which can be measured today by transcutaneous systems at the bedside is a valuable method for dynamic assessment of liver function and perfusion, and is regarded as a valuable prognostic tool in predicting survival of critically ill patients, presenting with sepsis, ARDS or acute liver failure.
Assuntos
Corantes/administração & dosagem , Corantes/farmacocinética , Verde de Indocianina/administração & dosagem , Verde de Indocianina/farmacocinética , Testes de Função Hepática/métodos , Fígado/fisiopatologia , Estado Terminal , Humanos , Fígado/cirurgia , Circulação Hepática , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/fisiopatologia , Transplante de Fígado , Monitorização Fisiológica/métodos , Período PerioperatórioRESUMO
Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5'-nucleotidase, Ecto5'NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care.
Assuntos
5'-Nucleotidase/fisiologia , Antígenos CD/fisiologia , Apirase/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Falência Hepática Aguda/fisiopatologia , 5'-Nucleotidase/genética , Animais , Antígenos CD/genética , Apirase/genética , Células Cultivadas , Humanos , Masculino , Camundongos , Transcrição Gênica , Regulação para CimaRESUMO
BACKGROUND: There is no standard therapy for acute liver failure. Hepatocyte transplantation has been proposed for temporary liver function support, while the injured liver regenerates or while waiting for transplantation. We have previously shown such efficacy for microencapsulated porcine hepatocytes in mice with fulminant liver failure. We aimed to establish a large animal model for fulminant liver failure to assess the efficacy of microencapsulated porcine hepatocytes in temporary liver function support. METHODS: The model was developed in baboons; for testing microencapsulated hepatocytes, the best condition was 75% hepatectomy and 60 min warm ischemia time. Fulminant liver failure was characterized by steep increases in liver biochemical parameters, severe steatosis, and massive hepatocyte necrosis during the first 10 days. Hepatocytes from miniature swine were microencapsulated in alginate-poly-l-lysine microspheres, and transplanted intraperitoneally immediately after hepatectomy and warm ischemia (80-120 mL packed hepatocytes in 200-350 mL microspheres, about 30%-50% of the baboon's native liver volume). RESULTS: In the control group, three of five animals were sacrificed after 6-10 days because of fulminant liver failure, and two of five animals recovered normal liver function and survived until elective euthanasia (28 days). In the treatment group of four animals, one animal developed liver failure but survived to 21 days, and three animals recovered completely with normal liver function. CONCLUSIONS: The results indicate that microencapsulated porcine hepatocytes provide temporary liver function support in baboons with fulminant liver failure. These data support development of this cell therapy product toward clinical trials in patients with acute liver failure.