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1.
Am J Pathol ; 190(2): 347-357, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31734229

RESUMO

Severe hepatic insults can lead to acute liver failure and hepatic encephalopathy (HE). Transforming growth factor ß1 (TGFß1) has been shown to contribute to HE during acute liver failure; however, TGFß1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFß1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess TSP-1 during acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1-/-) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurologic decline, and molecular analyses of TSP-1 and TGFß1 signaling were performed. AOM-treated mice had increased TSP-1 and TGFß1 mRNA and protein expression in the liver. TSP-1-/- mice administered AOM had reduced liver injury as assessed by histology and serum transaminase levels compared with C57Bl/6 AOM-treated mice. TSP-1-/- mice treated with AOM had reduced TGFß1 signaling that was associated with less hepatic cell death as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cleaved caspase 3 expression. TSP-1-/- AOM-treated mice had a reduced rate of neurologic decline, less cerebral edema, and a decrease in microglia activation in comparison with C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGFß1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.


Assuntos
Modelos Animais de Doenças , Encefalopatia Hepática/patologia , Falência Hepática Aguda/patologia , Trombospondina 1/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Azoximetano/toxicidade , Carcinógenos/toxicidade , Morte Celular , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/metabolismo , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
2.
J Ethnopharmacol ; 248: 112357, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31693919

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gogi berry is a traditional food supplement and medical herbal which has been widely used in Eastern Asian countries. Lycium barbarum polysaccharides (LBP) are the major active components of Gogi berry and have been proved to possess a lot of biological activities. AIM OF THE STUDY: We aimed to delineate the protective effect and mechanism of LBP on hepatic encephalopathy (HE). MATERIALS AND METHODS: We investigated the protective mechanism of LBP in a thioacetamide (TAA, intraperitoneally injected, 400 mg/kg) induced acute HE mice model. Key phenotypes of clinical HE were phenocopied in the mice model, including high mortality, severe hepatic histology injury, increased hepatic oxidative stress, apoptosis, enhanced circulating levels of pro-inflammatory cytokines and ammonia, suppressed tryptophan hydroxylase activity, and deficits in locomotor activity. RESULTS: The pathological alterations were effectively ameliorated by the oral administration with LBP (5 mg/kg, oral gavage, everyday), which were mediated by regulating MAPK pathways in both the liver and brain. Knockout of pro-inflammatory cytokines TNF-α or IL-6 effectively ameliorated impaired mice locomotor activity and MAPK activation in the brain. In an in vitro TNF-α-, IL-6-, or ammonia-induced microglia damaged cell model, cell injuries were evidently protected by the co-administration with LBP (50 µg/ml). CONCLUSION: LBP ameliorated the hepatic/brain injuries and impaired locomotor activities in a HE mice model. Pro-inflammatory cytokines may serve as communicating molecules linking the liver and brain for the HE pathogenesis, partly through MAPK regulation.


Assuntos
Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Encefalopatia Hepática/prevenção & controle , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Lycium , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Citocinas/deficiência , Citocinas/genética , Modelos Animais de Doenças , Frutas , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/patologia , Locomoção/efeitos dos fármacos , Lycium/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Transdução de Sinais , Tioacetamida , Fator de Necrose Tumoral alfa/metabolismo
3.
EBioMedicine ; 48: 539-553, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31648987

RESUMO

BACKGROUND: Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients. METHODS: Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy. FINDINGS: We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation. INTERPRETATION: Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE. FUNDING: Supported by the DFG, CRC974 "Communication and Systems Relevance in Liver Injury and Regeneration", Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).


Assuntos
Astrócitos/metabolismo , Autofagia , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/metabolismo , Animais , Astrócitos/ultraestrutura , Autopsia , Biópsia , Linhagem Celular , Células Cultivadas , Encefalopatia Hepática/complicações , Encefalopatia Hepática/patologia , Humanos , Concentração de Íons de Hidrogênio , Hiperamonemia/etiologia , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos , Neurônios/metabolismo , Neurônios/ultraestrutura , Ratos , Espécies Reativas de Oxigênio/metabolismo
4.
Curr Med Sci ; 39(5): 719-726, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612388

RESUMO

Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.


Assuntos
Insuficiência Hepática Crônica Agudizada/virologia , Ascite/virologia , Encefalopatia Hepática/virologia , Hepatite B Crônica/virologia , Hepatite E/virologia , Síndrome Hepatorrenal/virologia , Cirrose Hepática/virologia , Superinfecção/virologia , Insuficiência Hepática Crônica Agudizada/complicações , Insuficiência Hepática Crônica Agudizada/imunologia , Insuficiência Hepática Crônica Agudizada/patologia , Adulto , Idoso , Alanina Transaminase/sangue , Alanina Transaminase/imunologia , Ascite/complicações , Ascite/imunologia , Ascite/patologia , Bilirrubina/sangue , Bilirrubina/imunologia , China , Feminino , Encefalopatia Hepática/complicações , Encefalopatia Hepática/imunologia , Encefalopatia Hepática/patologia , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite E/complicações , Hepatite E/imunologia , Hepatite E/patologia , Vírus da Hepatite E/imunologia , Vírus da Hepatite E/patogenicidade , Hepatócitos/imunologia , Hepatócitos/patologia , Hepatócitos/virologia , Síndrome Hepatorrenal/complicações , Síndrome Hepatorrenal/imunologia , Síndrome Hepatorrenal/patologia , Humanos , Imunoglobulina G/sangue , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Superinfecção/complicações
5.
Sensors (Basel) ; 19(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443499

RESUMO

Biologically inspired to mammalian olfactory system, electronic noses became popular during the last three decades. In literature, as well as in daily practice, a wide range of applications are reported. Nevertheless, the most pioneering one has been (and still is) the assessment of the human breath composition. In this study, we used a prototype of electronic nose, called Wize Sniffer (WS) and based it on an array of semiconductor gas sensor, to detect ammonia in the breath of patients suffering from severe liver impairment. In the setting of severely impaired liver, toxic substances, such as ammonia, accumulate in the systemic circulation and in the brain. This may result in Hepatic Encephalopathy (HE), a spectrum of neuro-psychiatric abnormalities which include changes in cognitive functions, consciousness, and behaviour. HE can be detected only by specific but time-consuming and burdensome examinations, such as blood ammonia levels assessment and neuro-psychological tests. In the presented proof-of-concept study, we aimed at investigating the possibility of discriminating the severity degree of liver impairment on the basis of the detected breath ammonia, in view of the detection of HE at its early stage.


Assuntos
Gases/isolamento & purificação , Encefalopatia Hepática/diagnóstico , Fígado/química , Monitorização Fisiológica/métodos , Testes Respiratórios , Monóxido de Carbono/química , Monóxido de Carbono/isolamento & purificação , Nariz Eletrônico , Gases/química , Encefalopatia Hepática/patologia , Humanos , Hidrogênio/química , Hidrogênio/isolamento & purificação , Fígado/patologia
6.
Dig Dis ; 37(6): 509-517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170723

RESUMO

BACKGROUND: The pathogenesis of hepatic encephalopathy (HE) is only partially understood. Beside ammonia accumulation in brain, a proinflammatory component has been suggested as precipitating event. OBJECTIVES: To evaluate the role of cytokines in cirrhosis for development of HE. METHODS: Pro- and anti-inflammatory cytokine profiles were determined in rats with CCL4-induced cirrhosis and HE as well as in patients with cirrhosis either due to metabolic disorders or chronic hepatitis C virus (HCV) with various grades of concomitant HE and depression. RESULTS: In the rat model and human cirrhosis a proinflammatory cytokine pattern (elevation of interferon gamma, interleukin [IL]-1ß, IL-6) was registered which in humans correlated to the degree of HE and depression. The most prominent elevation of proinflammatory cytokines was observed in chronic HCV as an additional inflammatory stimulus. In all cases of cirrhosis a comparable background activation of anti-inflammatory cytokines (e.g., IL-4) was detected which was interpreted as a physiologic counterbalance mechanism. CONCLUSIONS: The degree of HE and depression correlated with a proinflammatory cytokine pattern. It suggests that beside ammonia elevation, inflammatory cytokines determine occurrence and severity of hepatic encephalopathies. Thus, it can be defined a preferential therapeutic target.


Assuntos
Encefalopatia Hepática/etiologia , Encefalopatia Hepática/patologia , Inflamação/complicações , Adulto , Idoso , Animais , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/metabolismo , Depressão/epidemiologia , Modelos Animais de Doenças , Feminino , Humanos , Incidência , Mediadores da Inflamação/sangue , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Ratos Wistar
7.
Metab Brain Dis ; 34(4): 1071-1076, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31089866

RESUMO

Hepatic encephalopathy (HE) is a frequent and debilitating complication of cirrhosis and its pathogenesis is not definitively clarified. Recent hypotheses focus on the possible existence of low-grade cerebral edema due to accumulation of osmolytes secondary to hyperammonemia. In the present study we investigated increases in cerebral water content by a novel magnetic resonance impedance (MRI) technique in cirrhosis patients with and without clinically manifest HE. We used a 3 T MRI technique for quantitative cerebral water content mapping in nine cirrhosis patients with an episode of overt HE, ten cirrhosis patients who never suffered from HE, and ten healthy aged-matched controls. We tested for differences between groups by statistical non-parametric mapping (SnPM) for a voxel-based spatial evaluation. The patients with HE had significantly higher water content in white matter than the cirrhosis patients (0.6%), who in turn, had significantly higher content than the controls (1.7%). Although the global gray matter water content did not differ between the groups, the patients with HE had markedly higher thalamic water content than patients who never experienced HE (6.0% higher). We found increased white matter water content in cirrhosis patients, predominantly in those with manifest HE. This confirms the presence of increasing degrees of low-grade edema with exacerbation of pathology. The thalamic edema in manifest HE may lead to compromised basal ganglia-thalamo-cortical circuits, in accordance with the major clinical symptoms of HE. The identification of the thalamus as particularly inflicted in manifest HE is potentially relevant to the pathophysiology of HE.


Assuntos
Edema Encefálico/patologia , Encéfalo/patologia , Encefalopatia Hepática/patologia , Cirrose Hepática/patologia , Água , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Edema Encefálico/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Encefalopatia Hepática/diagnóstico por imagem , Humanos , Cirrose Hepática/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
8.
Arch Pathol Lab Med ; 143(10): 1256-1258, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31063011

RESUMO

CONTEXT.­: Hepatic encephalopathy (HE) is associated with presence of type II astrocytes in the brain on the basis of observations made in single uncontrolled cases. This finding was subsequently demonstrated by in vitro studies with replication of microenvironment of HE by increase in ammonia levels. However, no human studies have been done correlating HE with type II astrocytes. OBJECTIVE.­: To determine the sensitivity and specificity of type II astrocytes in HE. DESIGN.­: This is a retrospective cohort study in which cases and controls were included. A database search was conducted to identify potential cases of hepatic encephalopathy during a 3-year period, as well as concomitant cases with altered mental status from other causes, liver disease, both, and neither. The presence of HE was determined according to standard clinical criteria, and a coronal section of basal ganglia was selected for examination from each case. Type II astrocytes were enumerated over 20 random high-power fields (HPFs). RESULTS.­: Twenty-one patients with HE were identified, with 35 patient controls (18 females, 38 males). Among the patients with HE there was a mean of 19.8 type II astrocytes in 20 HPFs. Patients with altered mental status without HE had an average of 7.2 type II astrocytes per 20 HPFs, and for those without altered mental status, the average was 2.8. For patients with hepatic insufficiency without HE, the average was 11, while for patients with normal hepatic function, the average was 4.1. Overall, for those without HE, the average was 5.4 type II astrocytes per 20 HPFs. CONCLUSIONS.­: At a cutoff of 5 or more type II astrocytes per 20 HPFs, sensitivity for HE was 85.7% and specificity was 68.6%. Alzheimer type II astrocytes were present in all cases of HE but were also present in a wide variety of patients without HE.


Assuntos
Doença de Alzheimer/diagnóstico , Astrócitos/patologia , Encefalopatia Hepática/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Autopsia , Encéfalo/patologia , Estudos de Coortes , Feminino , Encefalopatia Hepática/patologia , Humanos , Masculino , Registros Médicos , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
9.
Neuroscience ; 410: 1-15, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078686

RESUMO

The contribution of Dopamine (DA) to minimal hepatic encephalopathy (MHE) has been demonstrated. However, recent studies have revealed that cholesterol (CHO) treatment substantially increased the risk of dementia. The objectives of this study were to investigate whether CHO was induced by DA overload and its involvement in DA-induced cognitive impairment in MHE. Our study showed that DA treatment triggered CHO biosynthesis via the activation of JNK3/SREBP2 signaling pathway in primary cultured astrocytes. Conditioned media from DA-treated astrocytes increased CHO uptake by primary cultured neurons and disrupted synaptic formations; at the same time, inhibition of CHO synthesis and transportation from astrocytes diminished the disruption of synaptogenesis, which indicates the involvement of CHO in the perturbation of neural synaptogenesis in vitro. Secondary secretion of DA from primary cultured neurons was stimulated by CHO secreted from astrocytes. DA induced synergistic decreases of PPARγ/pERK/pCREB expressions in the presence of CHO in neurons, leading to synergistic synaptic impairment. Memory impairments were observed in MHE/DA-treated rats, which were partially rescued by atorvastatin (ATVS) treatment, confirming the involvement of CHO burden in vivo. Overall, our study suggests that DA overload triggers obvious CHO production from astrocytes. Excessive CHO in turn triggered neurons to secrete abundant DA and DA burden in combination with CHO overload elicit the cognitive decline and memory loss via PPARγ/ERK/CREB pathway in MHE.


Assuntos
Encéfalo/metabolismo , Colesterol/metabolismo , Dopamina/toxicidade , Encefalopatia Hepática/metabolismo , Neurogênese/fisiologia , Sinapses/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células Cultivadas , Dopamina/administração & dosagem , Encefalopatia Hepática/patologia , Injeções Intraventriculares , Lipogênese/efeitos dos fármacos , Lipogênese/fisiologia , Neurogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/patologia
10.
Dig Liver Dis ; 51(6): 850-855, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31031175

RESUMO

INTRODUCTION: Erectile dysfunction (ED) is common in patients with chronic diseases. It is evaluated using the International Index of Erectile Function (IIEF5) questionnaire. The relationship between ED and cirrhosis is complex. The aims of our study were (1) to assess the prevalence of ED in cirrhosis and (2) to evaluate factors associated with ED, with a special focus on minimal hepatic encephalopathy (MHE). METHODS: We performed a prospective, observational study. Patients with cirrhosis were invited to complete the IIEF5 questionnaire. The exclusion criteria were clinical hepatic encephalopathy (HE) and dementia. MHE was evaluated by the psychometric hepatic encephalopathy test score (PHES) and the critical flicker frequency (CFF). RESULTS: Between April 2016 and April 2017, 87 patients were included (age: 55 [51-57] years, Child-Pugh score: 8 [7-9], MELD score: 13 [11-16]. Minimal HE was diagnosed in 33% of the patients according to the PHES and in 44% of the patients according to the CFF. ED was diagnosed in 74/87 patients (85%) when compared to 12.5% in healthy controls (p < 0.001). In a multivariate analysis, the independent factors associated with ED were age, Child-Pugh and MELD scores. Significant correlations were identified between the IIEF5 and each component of the PHES. CONCLUSION: ED should be systematically screened in cirrhotics, especially in patients with MHE.


Assuntos
Disfunção Erétil/diagnóstico , Encefalopatia Hepática/complicações , Cirrose Hepática/complicações , Disfunção Erétil/etiologia , Fusão Flicker , Encefalopatia Hepática/patologia , Humanos , Cirrose Hepática/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Estudos Prospectivos , Índice de Gravidade de Doença
11.
Neuroradiology ; 61(6): 685-694, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30918990

RESUMO

PURPOSE: To investigate the diffusion kurtosis imaging (DKI) in early minimal hepatic encephalopathy (MHE) diagnosis and evaluate the correlations between changes in DKI metrics and cognitive performance. METHODS: We enrolled 116 cirrhosis patients, divided into non-HE (n = 61) and MHE (n = 55), and 46 normal controls (NCs). All patients underwent cognitive testing before magnetic resonance imaging. DKI metrics were calculated through whole-brain voxel-based analysis (VBA) and differences between the groups were assessed. Pearson correlation between the DKI metrics and cognitive performance was analysed. The receiver operating characteristic (ROC) curve was used to analyse the diagnostic efficiency of DKI metrics for MHE. RESULTS: MHE patients had significantly altered DKI metrics in a wide range of regions; lower fractional anisotropy (FA) and higher mean diffusivity (MD) are mainly located in the corpus callosum, left temporal white matter (WM), and right medial frontal WM. Furthermore, significantly altered kurtosis metrics included lower mean kurtosis (MK) in the corpus callosum and left thalamus, lower radial kurtosis (RK) in the corpus callosum, and lower axial kurtosis (AK) in the right anterior thalamic radiation. Alterations in axial diffusivity (AD), radial diffusivity (RD), and MD were closely correlated with cognitive scores. The ROC curves indicated AD in the forceps minor had the highest predictive performance for MHE in the cirrhosis patients (area under curve = 0.801, sensitivity = 77.05%, specificity = 74.55%). CONCLUSIONS: Altered DKI metrics indicate brain microstructure abnormalities in MHE patients, some of which may be used as neuroimaging markers for early MHE diagnosis.


Assuntos
Disfunção Cognitiva/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Encefalopatia Hepática/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Anisotropia , Biomarcadores/sangue , Estudos de Casos e Controles , Disfunção Cognitiva/patologia , Feminino , Encefalopatia Hepática/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Substância Branca/patologia
12.
Chem Biol Interact ; 299: 111-119, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500344

RESUMO

Hepatic encephalopathy (HE) is a serious neuropsychiatric syndrome due to either acute or chronic hepatic failure. This study aimed to investigate the possible neuroprotective effect of chrysin, a natural flavenoid on thioacetamide (TAA)-induced hepatic encephalopathy in rats. Also the effect of chrysin on motor impairment, cognitive deficits, oxidative stress, neuroinflammation, apoptosis and histopathological damage was assessed. HE was induced in Wistar rats by intraperitoneal (i.p.) injection of TAA (200 mg/kg) for three alternative days. Normal and control groups received the vehicle for 21 days. Chrysin was administered orally for 21 days (25, 50, 100 mg/kg) and starting from day 17, rats received i.p. dose of TAA (200 mg/kg) at three alternative days. Then behavioral, biochemical, histopathological and immunohistochemical analyses were conducted. Chrysin improved TAA-induced motor incoordination as it reduced final falling latency time in rotarod test, ameliorated cognitive deficits in object recognition test (ORT) and attenuated serum ammonia, hepatic liver enzymes namely, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) brain contents. Chrysin administration also reduced Toll-4 receptor (TLR-4) gene expression, caspase-3 protein expression, hepatic necrosis and astrocyte swelling. This study depicts that chrysin exerted neuroprotective effect in TAA-induced HE rats, evidenced by improvement of cognitive deficits, motor incoordination and histopathological changes such as astrocyte swelling and vacuolization; hallmarks in HE, via reducing hyperammonia, ameliorating hepatic function, in addition to its anti-oxidant, inactivation of TLR-4/NF-κB inflammatory pathway, and anti-apoptotic effects.


Assuntos
Flavonoides/uso terapêutico , Encefalopatia Hepática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Tioacetamida/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Caspase 3/metabolismo , Citocinas/metabolismo , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/patologia , Encefalopatia Hepática/veterinária , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Br J Biomed Sci ; 76(1): 24-28, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30392460

RESUMO

OBJECTIVE: Hepatic encephalopathy is a common consequence of liver cirrhosis, but diagnosis can be difficult as it is based on clinical criteria alone. We hypothesised that serum prealbumin, cholinesterase and retinol binding protein (RBP) can help support the diagnosis of hepatic encephalopathy. METHODS: We enrolled 306 cirrhotic patients (110 with encephalopathy), 100 chronic hepatitis B patients and 50 healthy controls, measuring routine liver function tests (ALT, AST, GGT, ALP, and bilirubin), albumin, prothrombin time, prealbumin, cholinesterase and RBP by routine methods. Logistic regression analysis and areas under the receiver operating characteristic curves (AUCs) were used to find predictive factors for hepatic encephalopathy. RESULTS: There were differences in all laboratory indices between the three groups (all p < 0.001). In univariate analysis, albumin, prothrombin time, prealbumin, cholinesterase and RBP were significantly altered in those with encephalopathy (p < 0.01), but only prealbumin, cholinesterase and RBP levels were significant predictors in multivariate analysis, and each was linked to the severity of liver fibrosis defined by the Child-Pugh score (all p < 0.001). The AUCs (95% CI) of prealbumin, cholinesterase and RBP for diagnosing liver cirrhosis with hepatic encephalopathy were comparable at 0.85 (81-90), 0.81 (0.76-0.85) and 0.81 (0.76-0.86), respectively (all p < 0.01). CONCLUSIONS: Serum prealbumin, cholinesterase and RBP levels are of potential clinical value in diagnosis of liver cirrhosis complicated by encephalopathy.


Assuntos
Colinesterases/sangue , Encefalopatia Hepática/diagnóstico , Hepatite B/diagnóstico , Cirrose Hepática/diagnóstico , Pré-Albumina/metabolismo , Proteínas Celulares de Ligação ao Retinol/sangue , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Encefalopatia Hepática/sangue , Encefalopatia Hepática/complicações , Encefalopatia Hepática/patologia , Hepatite B/sangue , Hepatite B/patologia , Hepatite B/virologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Curva ROC , gama-Glutamiltransferase/sangue
14.
Pediatr Neurol ; 90: 61-65, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391088

RESUMO

BACKGROUND: Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy. METHODS: We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed. RESULTS: Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years. CONCLUSIONS: In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered.


Assuntos
DNA Helicases/genética , DNA Mitocondrial , Encefalopatia Hepática/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Evolução Fatal , Feminino , Encefalopatia Hepática/diagnóstico por imagem , Encefalopatia Hepática/patologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Imagem por Ressonância Magnética , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/patologia
15.
Life Sci ; 218: 65-80, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578865

RESUMO

Hepatic encephalopathy (HE) is a critical clinical complication. There is a consensus that ammonia plays a pivotal role in the pathogenesis of HE. Ammonia is a neurotoxin which induces a wide range of functional disturbances in the central nervous system (CNS). On the other hand, HE is associated with the increased free radical formation, tissue inflammation, disturbed neurotransmission, astrocytes swelling, brain edema, and brain herniation. In view of the severe CNS complications ensued HE, potential therapeutic points of intervention need to be vigorously investigated. A role for CNS mitochondrial damage and energy crisis has been considered in HE. It has been found that ammonia induces mitochondrial impairment as a result of a multifaceted interaction of different signaling molecules. Hence, ammonia-induced mitochondrial injury and compromised brain energy metabolism might play a vital role in the pathogenesis of ammonia neurotoxicity. This review focuses on the concept that mitochondrial dysfunction and cellular energy crisis indeed plays a critical role in the pathogenesis of hyperammonemia-induced brain injury. Further, it will highlight the potential therapeutic value of mitochondrial protecting agents and energy providers in the management of HE. The data collected in this review might provide clues to new therapeutic interventions aimed at minimizing HE-associated complications.


Assuntos
Lesões Encefálicas/complicações , Encéfalo/efeitos dos fármacos , Encefalopatia Hepática/prevenção & controle , Hiperamonemia/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Taurina/farmacologia , Animais , Encéfalo/patologia , Metabolismo Energético , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/patologia , Humanos , Mitocôndrias/patologia
16.
Molecules ; 23(11)2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30380640

RESUMO

Swelling of retinal Müller cells is implicated in retinal edema and neuronal degeneration. Müller cell swelling is observed in patients with liver failure and is referred to as hepatic retinopathy. In the present study, we evaluated the effects of aloin, an anthraquinone-C-glycoside present in various Aloe species, on Müller cell dysfunction in a rat model of thioacetamide (TAA)-induced hepatic retinopathy. Experimental hepatic retinopathy was induced by three injections of TAA (200 mg/kg/day, intraperitoneal injection) for 3 days in rats. After the last injection of TAA, aloin (50 and 100 mg/kg) was orally gavaged for 5 days. The effects of aloin on the liver injury, serum ammonia levels, Müller cell swelling, glial fibrillary acidic protein (GFAP) expression, and gene expression of Kir4.1 and aquaporin-4 were examined. TAA-injected rats exhibited liver failure and hyperammonemia. In the TAA-injected rats, Müller cell bodies were highly enlarged, and GFAP, an indicator of retinal stress, was highly expressed in the retinas, indicating a predominant Müller cell gliosis. However, administration of aloin suppressed liver injury as well as Müller cell swelling through the normalization of Kir4.1 and aquaporin-4 channels, which play a key role in potassium and water transport in Müller cells. These results indicate that aloin may be helpful to protect retinal injury associated with liver failure.


Assuntos
Emodina/análogos & derivados , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Encefalopatia Hepática/complicações , Amônia/sangue , Animais , Aquaporina 4/genética , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Emodina/farmacologia , Células Ependimogliais/metabolismo , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/patologia , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/etiologia , Degeneração Retiniana/patologia , Tioacetamida/toxicidade
17.
ASN Neuro ; 10: 1759091418810583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30428281

RESUMO

Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (△Ψm), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 µM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition.


Assuntos
Encefalopatia Hepática/complicações , Encefalopatia Hepática/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nortriptilina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Encefalopatia Hepática/patologia , Marcação In Situ das Extremidades Cortadas , Testes de Função Hepática , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Atividade Motora/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Células PC12/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
EBioMedicine ; 37: 294-306, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30344125

RESUMO

BACKGROUND: Hepatic encephalopathy (HE), a severe neuropsychiatric complication, is associated with increased blood levels of ammonia and bile acids (BAs). We sought to determine (1) whether abnormally increased blood BAs in liver cirrhotic patients with HE is caused by elevation of apical sodium-dependent BA transporter (ASBT)-mediated BA reabsorption; and (2) whether increased BA reabsorption would exacerbate ammonia-induced brain injuries. METHODS: We quantitatively measured blood BA and ammonia levels in liver cirrhosis patients with or without HE and healthy controls. We characterized ASBT expression, BA profiles, and ammonia concentrations in a chronic liver disease (CLD) mouse model induced by streptozotocin-high fat diet (STZ-HFD) and an azoxymethane (AOM) - induced acute liver failure (ALF) mouse model. These two mouse models were treated with SC-435 (ASBT inhibitor) and budesonide (ASBT activator), respectively. FINDINGS: Blood concentrations of ammonia and conjugated BAs were substantially increased in cirrhotic patients with HE (n = 75) compared to cirrhotic patients without HE (n = 126). Pharmacological inhibition of the enterohepatic BA circulation using a luminal- restricted ASBT inhibitor, SC-435, in mice with AOM-induced ALF and STZ-HFD -induced CLD effectively reduced BA and ammonia concentrations in the blood and brain, and alleviated liver and brain damages. Budesonide treatment induced liver and brain damages in normal mice, and exacerbated these damages in AOM-treated mice. INTERPRETATION: ASBT mediated BA reabsorption increases intestinal luminal pH and facilitates conversion of intestinal ammonium to ammonia, leading to abnormally high levels of neurotoxic ammonia and cytotoxic BAs in the blood and brain. Inhibition of intestinal ASBT with SC-435 can effectively remove neurotoxic BAs and ammonia from the bloodstream and thus, mitigate liver and brain injuries resulting from liver failure.


Assuntos
Amônia/sangue , Ácidos e Sais Biliares/sangue , Doença Hepática Terminal/sangue , Encefalopatia Hepática/sangue , Falência Hepática Aguda/sangue , Animais , Linhagem Celular , Modelos Animais de Doenças , Doença Hepática Terminal/induzido quimicamente , Doença Hepática Terminal/patologia , Feminino , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/patologia , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Masculino , Camundongos , Pessoa de Meia-Idade
19.
Am J Med Sci ; 356(3): 296-303, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30286824

RESUMO

Approximately 3.7% of patients in primary care settings have chronic liver disease, and 18% with chronic liver disease in the specialty care setting have cirrhosis. For cirrhotic patients without complications, prognosis is generally favorable; increased morbidity and mortality are observed when complications (i.e., hepatic encephalopathy [HE]) occur. HE occurs in up to 70% of patients with cirrhosis. Neurologic signs in HE span a wide spectrum, from those not easily apparent (covert) to more clinically obvious signs (overt). Providers should consider overt HE in patients with cirrhosis and signs of impaired cognition, confusion, consciousness and/or personality changes, and/or impaired memory. Overt HE treatment includes identifying and treating precipitating factors and reducing bacterial-derived toxin loads. For acute overt HE, lactulose is first-line treatment. To prevent HE recurrence, lactulose plus rifaximin is recommended. Patients with cirrhosis and HE often present in primary care; recognizing and properly managing HE are important in this setting.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Encefalopatia Hepática , Lactulose/uso terapêutico , Cirrose Hepática , Rifaximina/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/microbiologia , Encefalopatia Hepática/patologia , Encefalopatia Hepática/fisiopatologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/microbiologia , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia
20.
Neuroimage Clin ; 20: 800-807, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30268989

RESUMO

Aberrant brain structural change in cirrhotic patients with or without hepatic encephalopathy is one of the most typical cases in voxel-based morphometry (VBM) studies. However, there exist inconsistent results regarding to the volume change of the thalamus. Furthermore, the relationship between thalamus structural change and cirrhotic symptoms has not yet been fully elucidated. To address these two issues, we repeated two VBM analyses in SPM and FreeSurfer and compared the two measurements with manually measured thalamic volumes. We also correlated the VBM results with clinical indexes related to cirrhosis to further investigate the relationship between thalamic structural change and liver cirrhosis. The inconsistent result of thalamic structural change was successfully reproduced in regard to the volume measurements of SPM and FreeSurfer. The manually measured results demonstrate an increase in the volume of the thalamus in cirrhotic patients compared to healthy controls, which differs from the results of FreeSurfer. The structural change of thalamus closely correlated with the blood biochemical indexes, including albumin levels, blood coagulation time, and AST/ALT ratio. All of these biochemical indexes are closely related to the severity of liver cirrhosis. Beyond all the results, this study also provides a good demonstration of the difference between multiple VBM measurements for clinicians.


Assuntos
Encefalopatia Hepática/patologia , Cirrose Hepática/complicações , Tálamo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Encefalopatia Hepática/complicações , Encefalopatia Hepática/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Tálamo/diagnóstico por imagem
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