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1.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G410-G418, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905026

RESUMO

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.


Assuntos
Bebedeira/complicações , Dieta Aterogênica , Fígado Gorduroso Alcoólico/etiologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Ácidos Graxos Trans , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/metabolismo , Dislipidemias/patologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Hepatomegalia/etiologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Cirrose Hepática Alcoólica/etiologia , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Alcoólica/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Ratos Sprague-Dawley
2.
PLoS One ; 14(6): e0218852, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31246992

RESUMO

BACKGROUND AND AIMS: Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. METHODS: This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naïve HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. RESULTS: The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses. CONCLUSIONS: In this cohort of Russians with HIV/HCV co-infection, who are anti-retroviral treatment naïve and have heavy alcohol use, we did not detect an association between zinc deficiency or zinc levels and advanced liver fibrosis.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Cirrose Hepática/etiologia , Zinco/deficiência , Adulto , Consumo de Bebidas Alcoólicas/sangue , Estudos de Coortes , Coinfecção , Estudos Transversais , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Hepatite C Crônica/sangue , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/epidemiologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/epidemiologia , Cirrose Hepática Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Federação Russa/epidemiologia , Adulto Jovem , Zinco/sangue
4.
Eur J Clin Invest ; 49(4): e13070, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30636282

RESUMO

BACKGROUND: The association between nonalcoholic fatty liver disease (NAFLD) and free triiodothyronine (FT3) in euthyroid subjects was in dispute. We aimed to investigate this issue in a population-based cohort study. MATERIALS AND METHODS: A total of 3144 euthyroid subjects at baseline from the Shanghai Nicheng Atherosclerosis Study were selected for the cross-sectional analysis, and 2089 subjects being followed up after 2.2 years were selected for the longitudinal analysis. NAFLD was diagnosed by ultrasound. The cut-off point of elevated alanine aminotransferase (ALT) level was 40 U/L. The FIB-4 index was used to assess the risk of advanced liver fibrosis. RESULTS: Age-adjusted mean levels of FT3 and FT3/free thyroxine (FT4) ratio were higher in subjects with NAFLD than those without NAFLD and linearly increased with a higher risk of NAFLD progression (assessed by levels of ALT and FIB-4 index) in euthyroid women but not in men. After adjustment for confounding variables, FT3 levels significantly increased with the presence of NAFLD (ß = 0.1, P < 0.001) and linearly increased with a higher risk of NAFLD progression in euthyroid women. After a 2.2-year follow-up, FT3 levels increased with the occurrence of NAFLD (mean change percentage: 1.4%) and decreased with the remission of NAFLD (mean change percentage: -2.7%) in euthyroid women. CONCLUSIONS: There are positive associations of FT3 levels with NAFLD and the risk of NAFLD progression in euthyroid women. The changes in FT3 levels with the alteration of NAFLD status may be an adaptive response to maintain energy and metabolic homeostasis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/etiologia , Tri-Iodotironina/metabolismo , Alanina Transaminase/metabolismo , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Cirrose Hepática Alcoólica/etiologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Remissão Espontânea , Fatores de Risco , Glândula Tireoide/fisiologia , Tireotropina/metabolismo , Tiroxina/metabolismo , Ultrassonografia
5.
Ann Agric Environ Med ; 25(3): 527-531, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30260179

RESUMO

The aim of the study was to determine serum concentrations of afamin and adropin in patients with alcoholic liver cirrhosis and to define their correlation with the stage of disease. The study included 99 patients with alcoholic cirrhosis from the region of Lublin, (Eastern Poland). Liver cirrhosis was diagnosed based on clinical features, history of heavy alcohol consumption, laboratory tests and abdominal ultrasonography. The control group consisted of 20 healthy individuals without liver disease who did not abuse alcohol. The serum afamin and adropin concentrations were determined using ELISA kits. The concentration of afamin was found to be significantly lower in patients with compensated alcoholic liver cirrhosis, i.e. P-Ch B (85.1±40.6 µg/ml) and P-Ch C (56.4±32.3 µg/ml) individuals, compared to the control group (135.9±43.6 µg/ml); p-value was <0.01 and <0.001, respectively. As far as adropin is concerned, a reverse relationship was demonstrated: the highest concentration was found in patients with P-Ch C (11.7±5.7 ng/ml) cirrhosis. Furthermore, the above concentration was significantly higher compared to patients with P-Ch A cirrhosis (7.2±2.8 ng/ml; p<0.05) and controls (7.5±2.6 ng/ml; p<0.05). The concentration of afamin decreases with the severity of alcoholic liver cirrhosis, which most likely results from impaired hepatic synthesis. Otherwise, the higher the stage of disease according to the Child-Pugh score, the higher the concentration of adropin.


Assuntos
Proteínas de Transporte/sangue , Glicoproteínas/sangue , Cirrose Hepática Alcoólica/sangue , Peptídeos/sangue , Adulto , Álcoois/efeitos adversos , Álcoois/metabolismo , Proteínas Sanguíneas/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Feminino , Glicoproteínas/genética , Humanos , Cirrose Hepática Alcoólica/diagnóstico por imagem , Cirrose Hepática Alcoólica/etiologia , Cirrose Hepática Alcoólica/genética , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polônia , Albumina Sérica Humana/genética , Índice de Gravidade de Doença , Ultrassonografia , Adulto Jovem
6.
Minerva Med ; 109(6): 457-471, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30221911

RESUMO

Alcohol consumption is one of the main risks to public health. Alcohol use disorders (AUDs) cause 80% of hepatotoxic deaths, and approximately 50% of cirrhosis is alcohol-related. The acceptable daily intake (ADI) for ethanol is 2.6 g/day, deduced from morbidity and mortality rates due to liver fibrosis. The relative risk of cirrhosis increases significantly for doses above 60 g/day for men and 20 g/day for women over a period of around 10 years. Twenty to 40% of steatosis cases will evolve into steatohepatitis/steatofibrosis, and 8 to 20% will evolve directly into liver cirrhosis. About 20 to 40% of steatohepatitis cases will evolve into cirrhosis, and 4 to 5% into hepatocellular carcinoma. This cascade of events evolves in 5 to 40 years, with the temporal variability caused by the subjects' genetic patterns and associated risk/comorbidity factors. Steatohepatitis should be considered "the rate limiting step:" usually, it can be resolved through abstinence, although for some patients, once this situation develops, it is not substantially modified by abstention and there is a risk of fibrotic evolution. Early detection of fibrosis, obtained by hepatic elastography, is a crucial step in patients with AUDs. Such strategy allows patients to be included in a detoxification program in order to achieve abstention. Drugs such as silybin, metadoxine, and adenosylmethionine can be used. Other drugs, with promising antifibrotic effects, are currently under study. In this review, we discuss clinical and pathogenetic aspects of alcohol-related liver fibrosis and present and future strategies to prevent cirrhosis.


Assuntos
Cirrose Hepática Alcoólica/diagnóstico , Cirrose Hepática Alcoólica/terapia , Ensaios Clínicos como Assunto , Feminino , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática Alcoólica/complicações , Cirrose Hepática Alcoólica/etiologia , Masculino
7.
J Vasc Interv Radiol ; 29(8): 1194-1202.e1, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29887183

RESUMO

PURPOSE: This study used the Oncopig Cancer Model (OCM) to develop alcohol-induced fibrosis in a porcine model capable of developing hepatocellular carcinoma. MATERIALS AND METHODS: Liver injury was induced in 8-week-old Oncopigs (n = 10) via hepatic transarterial infusion of 0.75 mL/kg ethanol-ethiodized oil (1:3 v/v). Feasibility was assessed in an initial Oncopig cohort (n = 5) by histologic analysis at 8 weeks after induction, and METAVIR results were compared to age- and sex-matched healthy controls (n = 5). Liver injury was then induced in a second OCM cohort (n = 5) for a time-course study, with post-induction disease surveillance via biweekly physical exam, lab analysis, and liver biopsies until 20 weeks after induction. RESULTS: In Cohort 1, 8-week post-induction liver histologic analysis revealed median METAVIR F3 (range, F3-F4) fibrosis, A2 (range, A2-A3) inflammation, and 15.3% (range, 5.0%-22.9%) fibrosis. METAVIR and inflammation scores were generally elevated compared to healthy controls (F0-F1, P = 0.0013; A0-A1, P = .0013; median percent fibrosis 8.7%, range, 5.8%-12.1%, P = .064). In Cohort 2, histologic analysis revealed peak fibrosis severity of median METAVIR F3 (range, F2-F3). However, lack of persistent alcohol exposure resulted in liver recovery, with median METAVIR F2 (range, F1-F2) fibrosis at 20 weeks after induction. No behavioral or biochemical abnormalities were observed to indicate liver decompensation. CONCLUSIONS: This study successfully validated a protocol to develop METAVIR F3-F4 fibrosis within 8 weeks in the OCM, supporting its potential to serve as a model for hepatocellular carcinoma in a fibrotic liver background. Further investigation is required to determine if repeated alcohol liver injury is required to develop an irreversible METAVIR grade F4 porcine cirrhosis model.


Assuntos
Carcinoma Hepatocelular/etiologia , Transformação Celular Neoplásica/patologia , Etanol , Óleo Etiodado , Cirrose Hepática Alcoólica/etiologia , Neoplasias Hepáticas/etiologia , Fígado/patologia , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Genes p53 , Genes ras , Cirrose Hepática Alcoólica/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Índice de Gravidade de Doença , Sus scrofa , Fatores de Tempo
10.
Alcohol ; 66: 1-7, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29277282

RESUMO

Laboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91 ± 0.01 and 0.88 ± 0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88 ± 0.01 for INR and 0.85 ± 0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85 units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288 units/L in men and 138 units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used.


Assuntos
Abstinência de Álcool , Consumo de Bebidas Alcoólicas/sangue , Bilirrubina/sangue , Ensaios Enzimáticos Clínicos , Coeficiente Internacional Normatizado , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/diagnóstico , Testes de Função Hepática/métodos , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/prevenção & controle , Área Sob a Curva , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Europa (Continente) , Feminino , Humanos , Cirrose Hepática Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Fatores Sexuais , Estados Unidos , gama-Glutamiltransferase/sangue
11.
Eur J Gastroenterol Hepatol ; 29(10): 1155-1160, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28727631

RESUMO

BACKGROUND: Several studies have suggested the efficacy of baclofen in reducing alcohol consumption, leading to a temporary recommendation for use in France. AIM: Our aim was to report our experience in using baclofen in alcohol-dependant patients with or without liver cirrhosis. PATIENTS AND METHODS: Consecutive patients from two liver and alcohol units were recruited over a 3-year period and received increasing doses of baclofen associated with social, psychological, and medical care. RESULTS: One hundred patients were treated, of whom 65 were cirrhotic. After 1 year, 86 patients were still being followed up. At a mean dosage of 40 mg/day (extremes: 30-210), the median daily alcohol consumption reduced from 80 to 0 g/day (P<0.001). Twenty patients drank a small amount of alcohol of up to 30 g/day and 44 patients were completely abstinent. These declarative results were associated with a significant improvement in alcohol-related biological markers in this 'low-consumption' group of 64 patients: the median γ-glutamyl transferase decreased from 3.9 to 2.0 UNL (P<0.001), the mean aspartate transaminase decreased from 2.6 to 1.2 UNL (P<0.001), and the mean corpuscular volume decreased from 101 to 93 µm (P<0.001). In cirrhotic patients, bilirubinemia decreased significantly from 22 to 11 µmol/l (P=0.026), prothrombin time increased from 68 to 77% (P<0.001), and albuminemia increased from 34.1 to 37.4 g/l (P<0.001). Twenty patients reported grades 1-2 adverse events. No liver or renal function deterioration occurred in cirrhotic patients. CONCLUSION: In our cohort, baclofen associated with a global care was very well tolerated even in cirrhotic patients. The marked reduction in alcohol consumption in 64 patients translated into a significant improvement in biological markers and in liver function tests. Baclofen could be very useful, especially in cases of severe alcoholic liver disease.


Assuntos
Abstinência de Álcool , Consumo de Bebidas Alcoólicas/prevenção & controle , Alcoolismo/tratamento farmacológico , Baclofeno/administração & dosagem , Agonistas dos Receptores de GABA-B/administração & dosagem , Cirrose Hepática Alcoólica/etiologia , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/complicações , Alcoolismo/diagnóstico , Alcoolismo/psicologia , Baclofeno/efeitos adversos , Feminino , França , Agonistas dos Receptores de GABA-B/efeitos adversos , Humanos , Cirrose Hepática Alcoólica/diagnóstico , Cirrose Hepática Alcoólica/psicologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Fatores de Tempo , Resultado do Tratamento
12.
Best Pract Res Clin Gastroenterol ; 31(2): 181-185, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28624106

RESUMO

The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Cirrose Hepática Alcoólica/etiologia , Transplante de Fígado/efeitos adversos , Qualidade de Vida/psicologia , Fumar/efeitos adversos , Humanos , Transplante de Fígado/mortalidade , Recidiva , Taxa de Sobrevida
13.
World J Gastroenterol ; 23(11): 2002-2011, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28373766

RESUMO

AIM: To explore the effect of interleukin (IL)-22 on in vitro model of alcoholic liver fibrosis hepatic stellate cells (HSCs), and whether this is related to regulation of Nrf2-keap1-ARE. METHODS: HSC-T6 cells were incubated with 25, 50, 100, 200 and 400 µmol/L acetaldehyde. After 24 and 48 h, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect proliferation of HSCs to choose the best concentration and action time. We used the optimal concentration of acetaldehyde (200 µmol/L) to stimulate HSCs for 24 h, and treated the cells with a final concentration of 10, 20 or 50 ng/mL IL-22. The cell proliferation rate was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The expression of nuclear factor-related factor (Nrf)2 and α-smooth muscle antigen was detected by western blotting and immunocytochemistry. The levels of malondialdehyde (MDA) and glutathione (GSH) were measured by spectrophotometry. RESULTS: In the MTT assay, when HSCs were incubated with acetaldehyde, activity and proliferation were higher than in the control group, and were most obvious after 48 h treatment with 200 µmol/L acetaldehyde. The number of cells in G0/G1 phases was decreased and the number in S phase was increased in comparison with the control group. When treated with different concentrations of IL-22, HSC-T6 cell activity and proliferation rate were markedly decreased in a dose-dependent manner, and cell cycle progression was arrested from G1 to S phase. Western blotting and immunocytochemistry demonstrated that expression of Nrf2 total protein was not significantly affected. Expression of Nrf2 nuclear protein was low in the control group, increased slightly in the model group (or acetaldehyde-stimulated group), and increased more obviously in the IL-22 intervention groups. The levels of MDA and GSH in the model group were significantly enhanced in comparison with those in the control group. In cells treated with IL-22, the MDA level was attenuated but the GSH level was further increased. These changes were dose-dependent. CONCLUSION: IL-22 inhibits acetaldehyde-induced HSC activation and proliferation, which may be related to nuclear translocation of Nrf2 and increased activity of the antioxidant axis Nrf2-keap1-ARE.


Assuntos
Antioxidantes/metabolismo , Células Estreladas do Fígado/metabolismo , Interleucinas/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Cirrose Hepática Alcoólica/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Acetaldeído/toxicidade , Animais , Elementos de Resposta Antioxidante , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Glutationa/análise , Cirrose Hepática Alcoólica/etiologia , Malondialdeído/análise , Camundongos , Ratos , Proteínas Recombinantes/metabolismo , Espectrofotometria
14.
Gut Liver ; 11(2): 173-188, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28274107

RESUMO

Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.


Assuntos
Gerenciamento Clínico , Cirrose Hepática Alcoólica/terapia , Hepatopatias Alcoólicas/terapia , Corticosteroides/uso terapêutico , Consumo de Bebidas Alcoólicas/efeitos adversos , Europa (Continente) , Humanos , Cirrose Hepática Alcoólica/etiologia , Cirrose Hepática Alcoólica/fisiopatologia , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/fisiopatologia , Transplante de Fígado
15.
J Hepatol ; 66(5): 930-941, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28040548

RESUMO

BACKGROUND & AIMS: In immune cells, constitutively and acutely produced type I interferons (IFNs) engage autocrine/paracrine signaling pathways to induce IFN-stimulated genes (ISGs). Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. We aimed to investigate ISG expression in systemic immune cells from patients with decompensated alcoholic cirrhosis, and its association with outcome. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients and heathy subjects were stimulated or not with lipopolysaccharide (LPS, an IFN inducer) or increasing concentrations of IFN-ß. The expression of 48 ISGs and ten "non-ISG" inflammatory cytokines were analyzed using RT-qPCR. RESULTS: We developed an 8-ISG signature (IFN score) assessing ISG expression. LPS-stimulated ISG induction was significantly lower in PBMCs from patients with cirrhosis compared to healthy controls. Non-ISGs, however, showed higher induction. Lower induction of ISGs by LPS was not due to decreased IFN production by cirrhotic PBMCs or neutralization of secreted IFN, but a defective PBMC response to IFN. This defect was at least in part due to decreased constitutive ISG expression. Patients with the higher baseline IFN scores and ISG levels had the higher risk of death. At baseline, "non-ISG" cytokines did not correlate with outcome. CONCLUSIONS: PBMCs from patients with decompensated alcoholic cirrhosis exhibit downregulated ISG expression, both constitutively and after an acute stimulus. Our finding that higher baseline PBMC ISG expression was associated with higher risk of death, suggests that constitutive ISG expression in systemic immune cells contributes to the prognosis of alcoholic cirrhosis. LAY SUMMARY: Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. Here we show that peripheral blood mononuclear cells (PBMCs) from patients with alcoholic cirrhosis exhibit a defect in interferon-stimulated genes (ISGs). We found that higher baseline ISG expression in PBMCs was associated with higher risk of death, revealing a probable contribution of ISG expression in immune cells to the outcome of alcoholic cirrhosis.


Assuntos
Interferon Tipo I/fisiologia , Leucócitos Mononucleares/imunologia , Cirrose Hepática Alcoólica/imunologia , Transdução de Sinais/fisiologia , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Cirrose Hepática Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Poli I-C/farmacologia
16.
Indian J Gastroenterol ; 36(1): 23-26, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28050823

RESUMO

BACKGROUND: Alcoholic hepatitis and cirrhosis although part of spectrum of alcoholic liver disease can have overlapping features, and differentiating them using clinical, biochemical, and imaging features is not always possible. Standard therapy for each differs, and steroid therapy while beneficial in alcoholic hepatitis may be detrimental in cirrhosis due to high infectious complications. We analyzed our experience with liver biopsy in patients with severe alcoholic hepatitis. METHODS: Male patients in the age group of 25-65 years who were clinically diagnosed with severe alcoholic hepatitis (DF > 32) were retrospectively analyzed and included in this study. All of them had undergone transjugular liver biopsy within the first 7 days of hospitalization. RESULTS: Thirty patients were included. Most were in the 35-55 age group. Jaundice was present in all patients with fever and tender hepatomegaly also being common. On histopathological evaluation, 33.3% (n = 10) suspected clinically to have alcoholic hepatitis had underlying cirrhosis. CONCLUSION: Cirrhosis is found in one third of patients with severe alcoholic hepatitis. This may alter our approach to management of this condition.


Assuntos
Biópsia/métodos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/patologia , Cirrose Hepática Alcoólica/diagnóstico , Cirrose Hepática Alcoólica/patologia , Fígado/patologia , Adulto , Idoso , Diagnóstico Diferencial , Febre/etiologia , Hepatite Alcoólica/complicações , Hepatomegalia/etiologia , Humanos , Icterícia/etiologia , Cirrose Hepática Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
18.
Clin Liver Dis ; 20(3): 419-27, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27373606

RESUMO

Liver disease from excessive alcohol consumption is an important cause of morbidity and mortality worldwide. There is a clear relationship between alcohol and a variety of health and socioeconomic problems. According to the World Health Organization, 3.3 million people die of alcohol-related causes annually. Despite public knowledge of its potential adverse effects, alcohol consumption and the morbidity and mortality from alcoholic liver disease (ALD) have increased. ALD comprises a spectrum of injury, including simple steatosis, acute alcoholic hepatitis, and cirrhosis. Rather than being distinct disease entities, these pathologic processes frequently overlap.


Assuntos
Hepatopatias Alcoólicas/etiologia , Consumo de Bebidas Alcoólicas , Fígado Gorduroso Alcoólico/etiologia , Feminino , Hepatite Alcoólica/etiologia , Humanos , Cirrose Hepática Alcoólica/etiologia , Hepatopatias Alcoólicas/epidemiologia , Masculino , Fatores de Risco
19.
Indian J Gastroenterol ; 35(3): 167-72, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27146041

RESUMO

BACKGROUND: Alcohol use is increasing in North East India and is important to estimate the influence of these changes in the epidemiology of alcohol related cirrhosis. METHODS: Among 1000 consecutive patients of cirrhosis, diagnosed by a combination of clinical, radiological and/or histopathological features, etiology was established by history of significant alcohol abuse, determining viral and autoimmune markers and by metabolic screening. Patients not confirmed to be cirrhotic were excluded from the study. All cases were studied to determine clinical features, complications, disease prognosis, and mortality. Alcoholic cirrhotics were then compared with nonalcohol etiology. RESULTS: 72.2 % alcoholic cirrhosis were compared with 27.8 % patients of nonalcohol etiology and alcoholic cirrhotics were younger (45 + 9.4 years vs. 47.9 + 12.5 years), predominantly males (M/F ratio 37:1 vs. 1.8:1) with significantly high incidence of jaundice (38.5 % vs. 30.5 %), night blindness (14.4 % vs. 3.6 %), ascites (76.3 % vs. 69.1 %), upper gastrointestinal bleed (46.4 % vs. 34.5 %), and hepatic encephalopathy (24.1 % vs. 10.4 %). Biochemical parameters that were significantly higher in alcoholics were mean bilirubin (4.7 + 8.7 vs. 3.1 + 4.7 mg/dL), AST/ALT ratio (2.03 vs. 1.4), gamma-glutaryl transaminase levels (209.7 + 37.9 vs. 93.9 + 14 IU/mL), and serum ammonia (75.1 + 55.7 vs. 52.1 + 45.4 mg/dL). Mean model for end-stage liver disease, scores, and Child C disease was significantly higher in alcoholics (18.6 + 7.7 vs. 15.6 + 6.4) and (54.1 % vs. 37 %), respectively, representing advanced disease at presentation. Mortality within 1 month was significantly higher among alcoholic cirrhosis (9.8 % vs. 3.2 %). CONCLUSION: Thus, alcoholic cirrhosis is of major concern in North East India as majority patients are in most productive age group and presented with advanced disease. Short-term mortality was high among alcoholic cirrhotics. Proper education and legislation are essential to mitigate the consequences of this disease.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Cirrose Hepática Alcoólica/epidemiologia , Cirrose Hepática Alcoólica/etiologia , Adolescente , Adulto , Fatores Etários , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Biomarcadores/sangue , Feminino , Educação em Saúde , Humanos , Índia/epidemiologia , Cirrose Hepática Alcoólica/diagnóstico , Cirrose Hepática Alcoólica/prevenção & controle , Masculino , Fatores Sexuais , Adulto Jovem
20.
Prog Transplant ; 26(1): 40-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27136248

RESUMO

CONTEXT: A large proportion of liver transplants (LTXs) are performed due to alcoholic liver disease (ALD) in the final stage of organ insufficiency. In order to list patients for LTX, transplant centers commonly require 6 months abstinence from alcohol. However, significant differences have been reported between alcohol intake as indicated by self-report and biochemical markers of alcohol. OBJECTIVE: In the present study, the usefulness of ethyl glucuronide analysis in hair (hETG) was examined during the evaluation procedure before listing patients with ALD for an LTX. DESIGN: Cross-sectional survey. SETTING: Psychosomatic evaluation. PATIENTS: Seventy patients with ALD prior to listing for an LTX. INTERVENTIONS: According to clinical assessment before listing patients with ALD (n = 233) for an LTX, hETG analysis was only performed in the patients who were assumed to deny or underreport their alcohol consumption (n = 70). MAIN OUTCOME MEASURES: The analysis of hETG by liquid chromatography-mass spectrometry, clinical interview. RESULTS: By hETG analyses, 27 (38.6%) of the 70 patients tested positive for ongoing alcohol consumption. CONCLUSIONS: Selective use of hETG based on the clinical interview rather than widespread screening is a possible way to detect excessive alcohol consumption in patients with ALD in the transplant setting. The primary evaluation of a patient's situation in its entirety should remain the superordinate standard procedure. An interdisciplinary approach to transplant candidates with an ALD is asked for.


Assuntos
Abstinência de Álcool , Glucuronatos/análise , Cabelo/química , Cirrose Hepática Alcoólica/cirurgia , Transplante de Fígado , Autorrelato , Adulto , Idoso , Alcoolismo/complicações , Biomarcadores , Cromatografia Líquida , Estudos Transversais , Feminino , Humanos , Entrevista Psicológica , Cirrose Hepática Alcoólica/etiologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade
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