Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.941
Filtrar
1.
Medicine (Baltimore) ; 99(39): e22428, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991479

RESUMO

Previous research has revealed a positive relationship between GSD, cholecystectomy and primary liver cancer (PLC). However, previous studies had several limitations including the retrospective design, narrow assessment of potential confounders and lack of competing risk models in time-to-event analyses. We conducted a large prospective cohort study to explore the relationship between GSD, cholecystectomy and PLC. A total of 95,021 participants who had not been diagnosed with PLC previously were enrolled from the Kailuan Cohort study. Demographic characteristics and biochemical parameters were recorded at baseline for all participants. We used Cox regression models and competing risk regression models to evaluate the association of GSD and cholecystectomy with the risk PLC. A total of 306 incidental PLC cases were identified during a median follow-up of 9.05 (8.75-9.22) years per participant. Compared with the normal group, the multivariable HRs (95%CI) for the association of GSD and cholecystectomy with PLC were 1.77 (1.05-2.94), 5.25 (1.95-14.17). In the CS model, the multivariable HRs (95%CI) was 1.76 (1.05-2.94) for the association of GSD and cholecystectomy with PLC and 5.25 (1.95-14.17) for GSD and cholecystectomy. Similar results were also obtained in the SD model with corresponding multivariate HRs (95%CI) of 1.75 (1.01-3.00), 5.22 (1.90-14.07) in the GSD group and cholecystectomy group, respectively. GSD and cholecystectomy were associated with an elevated risk of PLC.Registration number: ChiCTR-TNRC-11001489.


Assuntos
Colecistectomia/efeitos adversos , Cálculos Biliares/epidemiologia , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Cálculos Biliares/complicações , Cálculos Biliares/cirurgia , Humanos , Incidência , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco , Adulto Jovem
2.
Chem Biol Interact ; 327: 109176, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32534989

RESUMO

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.


Assuntos
Fígado Gorduroso Alcoólico/etiologia , PPAR alfa/metabolismo , Adiponectina/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação para Baixo , Etanol , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , PPAR alfa/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
3.
Medicine (Baltimore) ; 99(20): e20302, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443377

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for up to 90% of all primary hepatic malignancies; it is the sixth most common cancer and the second most common cause of cancer mortality worldwide. Numerous studies have shown that hepatitis B virus and its products, HBV integration, and mutation can induce HCC. However, the molecular mechanisms underpinning the regulation of HCC induced by HBV remain unclear. METHODS: We downloaded 2 gene expression profiling datasets, of HBV and of HCC induced by HBV, from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) between HCC and HBV were identified to explore any predisposing changes in gene expression associated with HCC. DEGs between HCC and adjacent healthy tissues were investigated to identify genes that may play a key role in HCC. Any overlapping genes among these DEGs were included in our bioinformatics analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of overlapping genes were performed using the Metascape online database; the protein-protein interaction (PPI) network was analyzed using the STRING online database; and we obtained the hub genes of the PPI network using Cytoscape software. An overall survival (OS) analysis of hub genes was performed using km-plotter and the gene expression profiling interactive analysis (GEPIA) online database. The expression levels of hub genes were determined using the TCGA and GEPIA databases. Finally, the relationships between hub genes and tumors were analyzed using the comparative toxicogenomics database (CTD). RESULTS: We identified 113 overlapping genes from the 2 datasets. Using functional and pathway analyses, we found that the overlapping genes were mainly related to the AMPK signaling pathway and cellular responses to cadmium ions. C8A, SPP2, KLKB1, PROZ, C6, FETUB, MBL2, HGFAC, C8B, and ANGPTL3 were identified as hub genes and C8A, SPP2, PROZ, C6, HGFAC, and C8B were found to be significant for survival. CONCLUSION: The DEGs re-analyzed between HCC and hepatitis B enable a systematic understanding of the molecular mechanisms of HCC reliant on hepatitis B virus.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Hepatite B/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Adenilato Quinase/genética , Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , Biologia Computacional , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Ontologia Genética , Hepatite C/complicações , Humanos , Neoplasias Hepáticas/genética , MicroRNAs , Mapas de Interação de Proteínas , Transdução de Sinais/fisiologia , Análise de Sobrevida
4.
Medicine (Baltimore) ; 99(20): e20326, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443384

RESUMO

The hypomethylation of the Cyclin D1 (CCND1) promoter induced by excess oxidative stress likely promotes the development of hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). We aimed to evaluate methylation status of the CCND1 promoter as a new plasma marker for the detection of HBV-HCC.We consecutively recruited 191 participants, including 105 patients with HBV-HCC, 54 patients with chronic hepatitis B (CHB), and 32 healthy controls (HCs). Using methylation-specific polymerase chain reaction, we identified the methylation status of the CCND1 promoter in plasma samples. We analyzed the expression levels of the CCND1 mRNA in peripheral blood mononuclear cells by using quantitative real-time PCR. We assessed the plasma levels of superoxide dismutase, 8-hydroxydeoxyguanosine and malondialdehyde by using enzyme-linked immunosorbent assays.Patients with HBV-HCC (23.81%) presented a reduced methylation frequency compared with patients with CHB (64.81%) or HCs (78.13%) (P < .001). When receiver operating characteristic curves were plotted for patients with HBV-HCC versus CHB, the methylation status of the CCND1 promoter yielded diagnostic parameter values for the area under the curve of 0.705, sensitivity of 76.19%, and specificity of 64.81%, thus outperforming serum alpha-fetoprotein (AFP), which had an area under the curve of 0.531, sensitivity of 36.19%, and specificity of 90.74%. Methylation of the CCND1 promoter represents a prospective diagnostic marker for patients with AFP-negative HBV-HCC and AFP-positive CHB. The expression levels of CCND1 mRNA was increased in patients with HBV-HCC compared with patients with CHB (Z = -4.946, P < .001) and HCs (Z = -6.819, P < .001). Both the extent of oxidative injury and antioxidant capacity indicated by the superoxide dismutase, 8-hydroxydeoxyguanosine and malondialdehyde levels were increased in patients with HBV-HCC. Clinical follow up of patients with HBV-HCC revealed a worse overall survival (P = .012, log-rank test) and a decreased progression-free survival (HR = 0.109, 95%CI: 0.031-0.384) for the unmethylated CCND1 group than methylated CCND1 group.Our study confirms that oxidative stress appears to correlate with plasma levels of CCND1 promoter methylation, and the methylation status of the CCND1 promoter represents a prospective biomarker with better diagnostic performance than serum AFP levels.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/fisiopatologia , Ciclina D1/metabolismo , Hepatite B Crônica/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/fisiopatologia , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Idoso , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Metilação de DNA/fisiologia , Detecção Precoce de Câncer , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Regiões Promotoras Genéticas/fisiologia , Estudos Prospectivos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Superóxido Dismutase/metabolismo , alfa-Fetoproteínas/análise
5.
Gastroenterol Clin North Am ; 49(2): 179-189, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389357

RESUMO

Viral hepatitis (A, B, C, D, and E) is the leading cause of inflammation of liver tissue (hepatitis). The disease burden associated with hepatitis A and E occurs shortly after infection; it is more severe among adults. With hepatitis A and E, the number of incident cases (new acute infections) is important from a public health perspective. Long-term hepatitis has been shown to cause cirrhosis and hepatocellular carcinoma in patients. The disease burden associated with hepatitis B, C, and D appears 10 to 20 years after infection. Thus, the prevalence of these infections is important from a public health perspective.


Assuntos
Saúde Global , Hepatite Viral Humana/epidemiologia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Feminino , Hepatite Viral Humana/complicações , Hepatite Viral Humana/mortalidade , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Masculino , Prevalência , Saúde Pública , Fatores de Tempo
6.
Gastroenterol Clin North Am ; 49(2): 201-214, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389359

RESUMO

Enhancing host immunity by vaccination to prevent hepatitis B virus (HBV) infection remains the most important strategy for global control of hepatitis B. Currently, 187 countries have in place infant hepatitis B vaccination programs. Hepatitis B surface antigen prevalence has decreased to less than 1% in children after successful implementation of universal HBV vaccination in newborns. The incidence of primary liver cancer in children, adolescents, and young adults has drastically decreased to near zero in birth cohorts receiving hepatitis B vaccination. Elimination of chronic hepatitis B by 2030 is not a mission impossible.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hepatite B/complicações , Hepatite B/diagnóstico , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B , Humanos , Incidência , Lactente , Recém-Nascido , Neoplasias Hepáticas/etiologia , Masculino , Prevalência , Adulto Jovem
7.
Gastroenterol Clin North Am ; 49(2): 239-252, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389361

RESUMO

Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.


Assuntos
Hepatite D/diagnóstico , Hepatite D/terapia , Adenina/análogos & derivados , Adenina/uso terapêutico , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Biomarcadores/sangue , Carcinoma Hepatocelular/etiologia , Saúde Global , Hepatite D/epidemiologia , Hepatite D/virologia , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/imunologia , Antígenos da Hepatite delta/imunologia , Humanos , Interferon alfa-2/uso terapêutico , Lamivudina/uso terapêutico , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Transplante de Fígado , Organofosfonatos/uso terapêutico , Prevalência , RNA Viral , Risco , Testes Sorológicos/métodos
8.
Gastroenterol Clin North Am ; 49(2): 215-238, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389360

RESUMO

Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.


Assuntos
Antivirais/administração & dosagem , Hepatite B/terapia , Imunomodulação , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Feminino , Hepatite B/complicações , Hepatite B/prevenção & controle , Hepatite B/virologia , Vírus da Hepatite B , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Prevalência
9.
Gastroenterol Clin North Am ; 49(2): 301-314, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389364

RESUMO

The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Qualidade de Vida , Resposta Viral Sustentada , Antivirais/administração & dosagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Doenças Cardiovasculares , Crioglobulinemia , Diabetes Mellitus , Quimioterapia Combinada , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Linfoma não Hodgkin
10.
AJR Am J Roentgenol ; 215(2): 382-389, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32432909

RESUMO

OBJECTIVE. The purposes of this study were to evaluate the outcome of new arterial phase enhancing nodules at MRI of cirrhotic livers, including clinical and imaging factors that affect progression to hepatocellular carcinoma (HCC), and to assess the diagnostic performance of Liver Imaging Reporting and Data System version 2018 (LI-RADSv2018) versus version 2017 (LI-RADSv2017) in categorizing these nodules. MATERIALS AND METHODS. A database search identified 129 new arterial phase enhancing, round, solid, space-occupying nodules in 79 patients with cirrhosis who underwent surveillance MRI. Three readers assessed the nodules for LI-RADS findings and made assessments based on the 2017 and 2018 criteria. Clinical information and laboratory values were collected. Outcome data were assessed on the basis of follow-up imaging and pathology results. Interreader agreement was assessed. Logistic regression and ROC curve analyses were used to assess the utility of the features for prediction of progression to HCC. RESULTS. Of the 129 nodules, 71 (55%) progressed to HCC. LI-RADSv2017 score, LIRADSv2018 score, and mild-to-moderate T2 hyperintensity were significant independent predictors of progression to HCC in univariate analyses. Serum α-fetoprotein level, hepatitis B or C virus infection as the cause of liver disease, and presence of other HCCs were significant predictors of progression to HCC in multivariate analyses. The rates of progression of LI-RADS category 3 and 4 observations were 38.1% and 57.6%, respectively, for LI-RADSv2017 and 44.4% and 69.9%, respectively, for LI-RADSv2018. CONCLUSION. New arterial phase enhancing nodules in patients with cirrhosis frequently progress to HCC. Factors such as serum α-fetoprotein level and presence of other HCCs are strong predictors of progression to HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/etiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etiologia , Fígado/diagnóstico por imagem , Fígado/patologia , Imagem por Ressonância Magnética/métodos , Artérias , Progressão da Doença , Feminino , Humanos , Cirrose Hepática/patologia , Imagem por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Estudos Retrospectivos
11.
Am J Gastroenterol ; 115(9): 1486-1495, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453046

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS: Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION: The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).


Assuntos
Carcinoma Hepatocelular/patologia , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Idoso , Carcinoma Hepatocelular/etiologia , Feminino , Humanos , Cirrose Hepática/complicações , Hepatopatias Alcoólicas/complicações , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores Sexuais
12.
Intern Med ; 59(7): 901-907, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238660

RESUMO

Objective The influence of interferon (IFN)-free direct-acting antiviral (DAA) on hepatocellular carcinoma (HCC) recurrence remains unclear. Previous retrospective analyses revealed that the time interval between HCC curative treatment and IFN-free DAA induction is the critical factor affecting HCC recurrence. Thus, this study aimed to examine the influence of DAA therapy on HCC recurrence considering this interval. Methods Factors contributing to HCC recurrence were retrospectively analyzed using a landmark time analysis and time-dependent extended Cox proportional hazards model. Patients After screening 620 patients who were diagnosed with primary HCC from January 2001 to December 2016, 76 patients with early-stage (primary and solitary) disease who received curative treatment and were positive for serum hepatitis C virus RNA were included. Results HCC recurrence was observed in 8 of 17 (47.1%) patients who had received IFN-free DAA therapy and 45 of 59 (76.3%) who had not. No significant difference was seen between the IFN-free DAA (-) and IFN-free DAA (+) groups in the landmark time and time-dependent Cox proportional hazards model analyses. However, IFN-free DAA therapy tended to decrease the HCC recurrence rate after curative treatment for primary HCC in patients with chronic hepatitis. In addition, IFN-free DAA therapy tended to decrease the second HCC recurrence rate after treatment for the first HCC recurrence. Conclusion Our results, with a consideration of the time interval between HCC curative treatment and IFN-free DAA induction, showed that IFN-free DAA therapy was not associated with early-stage HCC recurrence after curative treatment.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Feminino , Hepatite C Crônica/complicações , Humanos , Imunoterapia , Interferons/uso terapêutico , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Prevenção Secundária/métodos
13.
Metabolism ; 107: 154220, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32243868

RESUMO

BACKGROUND AND AIMS: Obesity, diabetes and associated non-alcoholic steatohepatitis (NASH) are rising risk factors for hepatocellular carcinoma (HCC). Macrophages are important immune cells involved in inflammation and tumour development. Macrophage inositol-requiring enzyme 1 alpha (IRE1α), an ER-stress protein, has been shown to be involved in macrophage cytokine production, and myeloid-specific IRE1α knock-out (myeloid IRE1α-KO) mice showed reduced weight gain during high-fat diet feeding. However, the effect of myeloid IRE1α on NASH and subsequent HCC development has not been examined. Here, we characterized the transcriptional profile of the hepatic macrophage population in a diabetes-NASH-HCC mouse model, and investigated the effect of myeloid-specific IRE1α deletion on the phenotype of hepatic macrophage subsets and experimental NASH-HCC development. METHODS: Mice with non-functional myeloid IRE1α were created by crossing Ire1a floxed mice with Lysm-Cre mice. Two-day old myeloid IRE1α-KO and wild type (WT) mice were subcutaneously injected with streptozotocin (STZ), and male mice were fed a high-fat, -sucrose, -cholesterol diet (Western diet, WD) from the age of 4 weeks until 21 weeks. Control myeloid IRE1α-KO and WT mice received a PBS injection and were fed a matched control diet. These mice were evaluated for obesity, diabetes, NASH and HCC. The hepatic macrophage population was evaluated by flow cytometry and RNA sequencing on FACS-isolated macrophage subsets. RESULTS: STZ-injection and WD feeding resulted in an impaired glucose tolerance, advanced NASH with fibrosis, and HCC development. Myeloid IRE1α-KO STZ mice showed lower fasting glucose levels at the start of WD feeding, and an improved glucose tolerance and attenuated HCC development after 17 weeks of WD feeding despite a similar degree of liver steatosis and inflammation compared to WT mice. Transcriptomic analysis of WT liver Kupffer cells, macrophages and monocytes revealed phenotypical changes in those cell subsets during NASH-HCC development. Isolated liver Kupffer cells and macrophages from mice with a myeloid IRE1α deletion showed downregulated pathways involved in immune system activation and metabolic pathways (only in Kupffer cells), whereas pathways involved in cell division and metabolism were upregulated in monocytes. These transcriptional differences were attenuated during NASH-HCC development. CONCLUSION: Our results show that myeloid-specific IRE1α deletion results in an altered transcriptional profile of hepatic macrophages and dampens diabetes-induced NASH-HCC development, possibly by attenuated diabetes induction.


Assuntos
Diabetes Mellitus Experimental/complicações , Endorribonucleases/genética , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Proteínas Serina-Treonina Quinases/genética , Animais , Glicemia/metabolismo , Dieta Ocidental , Intolerância à Glucose/prevenção & controle , Macrófagos do Fígado/patologia , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas Experimentais/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ativação Transcricional
14.
Indian J Gastroenterol ; 39(1): 9-21, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32291578

RESUMO

Evidence accumulates to implicate a role for the gut microbiota in non-alcoholic fatty liver disease (NAFLD)-a disorder that has reached almost epidemic proportions around the globe. For some time a disturbance in the gut microbiome, small intestinal bacterial overgrowth (SIBO), has been described among patients with liver disease, in general, and in the development and progression of NAFLD to nonalcoholic steatohepatitis (NASH), decompensated liver disease and hepatocellular cancer (HCC), in particular. More recently and permitted by the advent of high-throughput sequencing and allied molecular techniques, a much more detailed analysis of gut microbiota in NAFLD and NASH has become possible. In animal models, several mechanisms have been delineated which reveal how gut bacteria and their products could promote steatosis, hepatic inflammation, fibrosis, cirrhosis, and carcinogenesis. For understandable reasons evidence from human studies is less complete, but here again a plausible case is beginning to emerge to incriminate microbiota in NAFLD and NASH pathogenesis. Therapeutic interventions based on the modulation of the microbiome have been explored to some extent, but their application to everyday medical practice is still in the future.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica/microbiologia , Carcinoma Hepatocelular/etiologia , Progressão da Doença , Humanos , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia
15.
J Hepatol ; 73(2): 441-445, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32298769

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has shattered the meticulously developed processes by which we delivered quality care for patients with cirrhosis. Care has been transformed by the crisis, but enduring lessons have been learned. In this article, we review how COVID-19 will impact cirrhosis care. We describe how this impact unfolds over 3 waves; i) an intense period with prioritized high-acuity care with delayed elective procedures and routine care during physical distancing, ii) a challenging 'return to normal' following the end of physical distancing, with increased emergent decompensations, morbidity, and systems of care overwhelmed by the backlog of deferred care, and iii) a protracted period of suboptimal outcomes characterized by missed diagnoses, progressive disease and loss to follow-up. We outline the concrete steps required to preserve the quality of care provided to patients with cirrhosis. This includes an intensification of the preventative care provided to patients with compensated cirrhosis, proactive chronic disease management, robust telehealth programs, and a reorganization of care delivery to provide a full service of care with flexible clinical staffing. Managing the pandemic of a serious chronic disease in the midst of a global infectious pandemic is challenging. It is incumbent upon the entire healthcare establishment to be strong enough to weather the storm. Change is needed.


Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Assistência à Saúde/tendências , Cirrose Hepática/terapia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Qualidade da Assistência à Saúde/tendências , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Tomada de Decisão Clínica/métodos , Infecções por Coronavirus/virologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Equipe de Assistência ao Paciente , Pneumonia Viral/virologia , Telemedicina/métodos
16.
Adv Exp Med Biol ; 1238: 39-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32323179

RESUMO

Chronic liver injury mainly comprises viral hepatitis, fatty liver disease, autoimmune hepatitis, cirrhosis and liver cancer. It is well established that gut microbiota serves as the key upstream modulator for chronic liver injury progression. Indeed, the term "gut-liver axis" was mostly applied for chronic liver injury. In the current chapter, we will summarize the relationship between gut microbiota and chronic liver injury, including the interaction between them based on latest clinic and basic research.


Assuntos
Microbioma Gastrointestinal , Hepatopatias/etiologia , Fígado/lesões , Fígado/patologia , Doença Crônica , Humanos , Cirrose Hepática/etiologia , Hepatopatias/patologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia
17.
Am J Gastroenterol ; 115(6): 859-866, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32235146

RESUMO

OBJECTIVES: Frailty and sarcopenia are known risk factors for adverse liver transplant outcomes and mortality. We hypothesized that frailty or sarcopenia could identify the risk for common serious transplant-related adverse respiratory events. METHODS: For 107 patients (74 men, 33 women) transplanted over 1 year, we measured frailty with gait speed, chair stands, and Karnofsky Performance Scale (KPS) and sarcopenia with Skeletal Muscle Index on computed tomography at L3. We recorded the stress-tested cardiac double product as an index of cardiac work capacity. Outcomes included days of intubation, aspiration, clinical pneumonia, reintubation/tracheostomy, days to discharge, and survival. We modeled the outcomes using unadjusted regression and multivariable analyses controlled for (i) age, sex, and either Model for End-Stage Liver Disease-Na (MELDNa) or Child-Turcotte-Pugh scores, (ii) hepatocellular carcinoma status, and (iii) chronic obstructive pulmonary disease and smoking history. Subgroup analysis was performed for living donor liver transplant and deceased donor liver transplant recipients. RESULTS: Gait speed was negatively associated with aspiration and pulmonary infection, both in unadjusted and MELDNa-adjusted models (adjusted odds ratio for aspiration 0.10 [95% confidence interval [CI] 0.02-0.67] and adjusted odds ratio for pulmonary infection 0.12 [95% CI 0.02-0.75]). Unadjusted and MELDNa-adjusted models for gait speed (coefficient -1.47, 95% CI -2.39 to -0.56) and KPS (coefficient -3.17, 95% CI -5.02 to -1.32) were significantly associated with shorter intubation times. No test was associated with length of stay or need for either reintubation or tracheostomy. DISCUSSION: Slow gait speed, an index of general frailty, indicates significant risk for post-transplant respiratory complications. Intervention to arrest or reverse frailty merits exploration as a potentially modifiable risk factor for improving transplant respiratory outcomes.


Assuntos
Fragilidade/epidemiologia , Cirrose Hepática/cirurgia , Transplante de Fígado , Pneumonia/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Respiração Artificial/estatística & dados numéricos , Aspiração Respiratória/epidemiologia , Velocidade de Caminhada , Idoso , Extubação , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , Feminino , Fragilidade/diagnóstico , Fragilidade/fisiopatologia , Humanos , Intubação Intratraqueal , Avaliação de Estado de Karnofsky , Tempo de Internação , Cirrose Hepática/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Desempenho Físico Funcional , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Traqueostomia
19.
J Hepatol ; 73(2): 441-445, 2020 08.
Artigo em Inglês | MEDLINE | ID: covidwho-164705

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has shattered the meticulously developed processes by which we delivered quality care for patients with cirrhosis. Care has been transformed by the crisis, but enduring lessons have been learned. In this article, we review how COVID-19 will impact cirrhosis care. We describe how this impact unfolds over 3 waves; i) an intense period with prioritized high-acuity care with delayed elective procedures and routine care during physical distancing, ii) a challenging 'return to normal' following the end of physical distancing, with increased emergent decompensations, morbidity, and systems of care overwhelmed by the backlog of deferred care, and iii) a protracted period of suboptimal outcomes characterized by missed diagnoses, progressive disease and loss to follow-up. We outline the concrete steps required to preserve the quality of care provided to patients with cirrhosis. This includes an intensification of the preventative care provided to patients with compensated cirrhosis, proactive chronic disease management, robust telehealth programs, and a reorganization of care delivery to provide a full service of care with flexible clinical staffing. Managing the pandemic of a serious chronic disease in the midst of a global infectious pandemic is challenging. It is incumbent upon the entire healthcare establishment to be strong enough to weather the storm. Change is needed.


Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Assistência à Saúde/tendências , Cirrose Hepática/terapia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Qualidade da Assistência à Saúde/tendências , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Tomada de Decisão Clínica/métodos , Infecções por Coronavirus/virologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Equipe de Assistência ao Paciente , Pneumonia Viral/virologia , Telemedicina/métodos
20.
Chem Biol Interact ; 323: 109054, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32217109

RESUMO

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) has been associated with fibrosis that may progress to cirrhosis. The purpose of this study was to examine hepatocytes and perisinusoidal cells in liver biopsies of 3 families (3 males and 4 females) with non-cirrhotic and cirrhotic NASH to determine unique histological changes during a period of 2-7 years from diagnosis. METHODS: In this study, hepatocytes, stellate cells and Kupffer cells were analyzed using light and electron microscopy, and immunohistochemistry with specific anti-macrophage antibody staining of liver biopsies. RESULTS: Body mass index of all patients was over 28, and all viral, metabolic markers were negative. Alcohol consumption was insignificant. In all liver biopsies, diffuse, non-zonal macrovesicular steatosis involved 40-70% of liver samples. The lobular hepatocytes showed prominent ballooning hepatocyte degeneration. No Mallory Denk hyaline bodies (MDBs) were observed in three of the patients. MDBs developed in ballooned hepatocytes of four individuals that also presented foci of lobular inflammation. The apoptotic bodies were stained by cytokeratin 18. The trichrome stain revealed portal to portal bridging fibrosis. In one family, there was a three-fold increase in relative numbers of perisinusoidal macrophages in the older sister with NASH compared to livers of the younger siblings. The special finding in livers of patients with NASH was accumulation of groups of perisinusoidal macrophages, which was not associated with focal necrosis. CONCLUSION: Perisinusoidal macrophages appear to accumulate in NASH. It is possible that collections of macrophages are a response to chronic portal endotoxemia or lipotoxic activation of immuno-mediators. The persistent activation of these macrophages could lead to the chronic release of pro-inflammatory cytokines and contribute to chronic inflammation, fibrosis and cirrhosis leading to HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Adulto , Biópsia , Carcinoma Hepatocelular/patologia , Feminino , Células Estreladas do Fígado/patologia , Humanos , Macrófagos do Fígado/patologia , Gotículas Lipídicas/metabolismo , Fígado/patologia , Fígado/ultraestrutura , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA