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BACKGROUND: This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). METHODS: This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. RESULTS: Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥ 23 kg/m2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037-8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Common Estimate OR: 2.531; 95% CI: 1.388-4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772-9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398-6.210; P = 0.004) after the adjustments of the BMI and diabetes. CONCLUSIONS: Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.
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Resistencia a la Insulina , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Biopsia , China/epidemiología , Estudios Transversales , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiologíaRESUMEN
Autophagy is an intracellular recycling and degradation process for regulating cell survival and drug resistance. Non-alcoholic steatohepatitis (NASH) is becoming a widespread disease in developing countries. However, the role of autophagy in NASH has not yet been fully elucidated. The present study determined that signal transducer and activator of transcription 3 (STAT3), in the inflammation and autophagy regulation, was the key in the progression of NASH. In NASH mouse and cell models, STAT3 mRNA and protein expressions were significantly increased, while the induction of autophagy was radically decreased. Furthermore, the effects of metformin on STAT3 expression level and NASH inflammation were investigated. The current results showed that metformin activated autophagy and decreased the mRNA expressions of inflammatory cytokines, IL-1ß, IL-6, and TNF-α via inhibition of the STAT3 mRNA and protein expression. The siRNA targeting STAT3 activated autophagy and inhibited the NASH inflammatory response by reducing the mRNA expressions of the inflammatory cytokines in vivo and in vitro. The correlation between autophagy and inflammation was also explored. Autophagy induced by metformin attenuated the inflammatory response. This phenomenon of inflammation reduction was partially restored by treatment with the autophagy inhibitor 3-methylindole (3-MA). In conclusion, this study demonstrated that metformin alleviated the inflammatory response in the liver and the hepatocyte of the NASH model via STAT3-mediated autophagy induction. This mechanism provides a strategy for targeting the NASH inflammatory response.
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Autofagia/efectos de los fármacos , Inflamación/tratamiento farmacológico , Metformina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Factor de Transcripción STAT3/inmunología , Animales , Inflamación/complicaciones , Inflamación/inmunología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/inmunologíaRESUMEN
BACKGROUND: The relationship between resistin and non-alcoholic steatohepatitis (NASH) is not clear, some studies claimed that serum resistin levels were associated with neither the presence of NASH nor its severity, others declared that serum resistin was related with inflammation and fibrosis in NASH. Our animal study verified that the distribution of resistin in the liver is correlated with inflammation in NASH. However, there is no pertinent study in humans. METHODS: Thirty patients with NASH, 28 simple steatosis, and 43 controls were recruited. Blood was collected for resistin, liver chemistries, fasting insulin and some metabolic parameters. Liver histology was scored according to NAFLD activity scoring system. Hepatic resistin expression was examined by real-time polymerase chain reaction, immunohistochemistry. Resistin protein expression was confirmed by western blotting in 13 patients with concomitant NAFLD and gallstone. RESULTS: Serum resistin was significantly elevated in both NASH and simple steatotic subjects compared with controls (all P < 0.05). Hepatic resistin was significantly increased in NASH patients in both mRNA and protein levels than those in simple steatosis and control subjects (all P < 0.05). Both serum and hepatic resistin had a correlation with obesity, but not with insulin resistance. The distribution of resistin positive cells was predominantly in perisinusoidal cells (such as Kupffer cells and hepatic stellate cells) in human NASH. Multivariate analysis revealed that waist-hip ratio, higher serum triglyceride, and hyperresistinemia were independent factors related to higher grade of steatosis; whereas hepatic resistin and serum cytokeratin predict NASH and severity of liver fibrosis. CONCLUSIONS: Hepatic resistin overexpression in NASH patients is associated with the severity of liver inflammation and fibrosis. Liver-derived resistin may be involved in the pathogenesis of human NASH.
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Hígado Graso/sangre , Hígado Graso/patología , ARN Mensajero/análisis , Resistina/sangre , Adulto , Estudios de Casos y Controles , Hígado Graso/metabolismo , Femenino , Células Estrelladas Hepáticas/química , Humanos , Resistencia a la Insulina , Queratinas/sangre , Macrófagos del Hígado/química , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Obesidad/metabolismo , Estudios Prospectivos , Resistina/análisis , Resistina/genética , Triglicéridos/sangre , Regulación hacia Arriba , Relación Cintura-CaderaRESUMEN
BACKGROUND: The complexity of immunoglobulin G4 (IgG4)-related diseases and their potential connection to hematologic malignancies remains unclear. This article provided a review of the diagnosis and treatment of a patient with IgG4-related sclerosing cholangitis (SC) and essential thrombocythemia (ET), along with an analysis of relevant literature to enhance comprehension of this disease. CASE SUMMARY: A 56-year-old male was admitted to two hospitals with deteriorating jaundice and pruritus prior to hospitalization. Beyond our expectations, the patient was first diagnosed with IgG4-SC and ET with the Janus kinase 2 V617F mutation. Interestingly, the administration of acetate prednisone significantly resulted in improvements in both IgG4-SC and ET. Clinicians need to pay attention to immune disorders and inflammation as they contribute to the development of various disease phenotypes. CONCLUSION: When IgG4-SC is suspected without histopathological evidence, diagnostic therapy and long-term regular follow-up can lead to positive treatment outcomes. Clinicians should be mindful of the potential presence of concurrent hematologic diseases in patients with immune disorders.
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BACKGROUND: Stromal cell derived factor-1 (SDF-1) plays a pivotal role in the recruitment of stem cells to injured livers. However, the changes of SDF-l in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) have yet to be elucidated. AIM: To study the SDF-1 changes in patients with HBV-related ACLF. METHODS: 30 patients with HBV-related ACLF, 27 patients with chronic hepatitis B and 20 healthy individuals are involved in our study. The SDF-l mRNA expression in liver tissue was detected by quantitative real-time polymerase chain reaction. Immunohistochemical staining was performed to illustrate the expression of SDF-l, CXC receptor 4 (CXCR4) and Ki67. The serum SDF-l concentrations were also detected by enzyme-linked immunosorbent assays. RESULTS: The expression of SDF-1 mRNA from ACLF patients was remarkably higher than that from other patients (both P < 0.05). The expression of SDF-l, CXCR4 and Ki67 from ACLF were the highest among the three groups (all P < 0.01). The serum SDF-l levels in ACLF patients were significantly lower than that in other patients (both P < 0.01). Moreover, in ACLF patients, the serum SDF-1 Levels were positively correlated with serum total bilirubin and international normalized ratio. In addition, the serum SDF-l levels in survival were significantly lower compared with the non-survivals (P < 0.05). The area under the curve for the serum SDF-1 level in predicting 28-d mortality was 0.722 (P < 0.05). CONCLUSION: This study provides the SDF-1 changes in patients with HBV-related ACLF. The SDF-1 Level at admission may serve as a promising prognostic marker for predicting short-term prognosis.
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BACKGROUND: To investigate whether "binge" and escalating alcohol exposure in the rat influences the development of pathological liver injury. METHODS: Time courses for the formation of eicosanoids by cyclooxygenase (COX), oxidative stress and nitrosative stress production, expression of hypoxia-inducible factor 1 (HIF-1), cytokines, hepatic tissue necroinflammation, and fibrosis were assessed in rats during 16 weeks of daily alcohol gavage. RESULTS: In this model of binge and escalating levels of alcohol, hepatic steatosis, necrosis, and inflammation as well as fibrosis were increased over the 16-week period. The levels of COX-2, oxidative stress, nitrosative stress, HIF-1, proinflammatory mediators (tumor necrosis factor-α, interleukin 1(ß) [IL-1(ß) ], IL-6), and procollagen-I were increased over the 16-week period. The content of IL-10 in rat serum increased at the end of 4 and 8 weeks but decreased thereafter and was significantly decreased at 12 and 16 weeks. CONCLUSIONS: A rat model of alcoholic liver disease (ALD) with long-term binge and escalating ethanol exposure was developed. Our data support the hypothesis that enhanced eicosanoid production by COX, oxidative stress and nitrosative stress, HIF-1, and the imbalance between pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of ALD.
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Consumo Excesivo de Bebidas Alcohólicas/patología , Etanol/efectos adversos , Inflamación/patología , Cirrosis Hepática/patología , Hígado/efectos de los fármacos , Hígado/patología , Animales , Consumo Excesivo de Bebidas Alcohólicas/sangre , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/inducido químicamente , Mediadores de Inflamación/metabolismo , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Masculino , Necrosis/inducido químicamente , Necrosis/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Procolágeno/metabolismo , Ratas , Ratas Wistar , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
OBJECTIVE: To investigate the dynamic changes that occur in T cell subsets, particularly involving the surface expression of programmed death 1 (PD-1), in response to pegylated (Peg)-interferon (IFN) a-2a therapy in patients with chronic hepatitis C virus (HCV) infection. METHODS: Twenty-five patients with HCV genotype 1b chronic infection and 10 healthy controls were enrolled in the study. All the HCV patients received combination antiviral therapy of Peg-IFNa-2a (180 mug/week) plus ribavirin. At treatment weeks 0 (baseline), 4, 12, 24 and 48, the level of PD-1 protein expression on the surface of total peripheral CD8+ and CD4+ T cells was determined by flow cytometry and the level of PD-1 mRNA expression in peripheral blood mononuclear cells (PBMCs) was determined by reverse transcription-polymerase chain reaction. Independent student's t-test were used to compare mean values between the two groups, repeat measure variance analysis was used to compare mean values among multiple groups, and Pearson's correlation coefficient was used to assess correlation significance. RESULTS: Over the course of antiviral therapy, the proportions of CD4+ T cells and CD8+ T cells, as well as the CD4+/CD8+ ratio, increased (F = 81.23, 39.28, and 7.01 respectively; all P less than 0.01). In contrast, the PD-1 protein expression frequency on CD4+ T cells and CD8+ T cells significantly declined (F = 100.11 and 158.40 respectively; all P less than 0.01). The PD-1-mRNA expression level in PBMCs was: 1.40+/-0.26 at baseline, 1.30+/-0.27 at week-4, 1.14+/-0.18 at week-12, 1.06+/-0.26 at week-24, and 0.83+/-0.25 at week-48 (F = 20.09; P less than 0.01). A positive correlation existed between the PD-1 protein expression frequencies on CD4+ T cells and CD8+ T cells and the HCV RNA load detected at baseline (r = 0.82 and 0.75 respectively; all P less than 0.01). CONCLUSION: The ability of Peg-IFN-a-2a-based antiviral therapy to suppress HCV replication may involve reduction of PD-1 protein expression on the surface of CD8+ T cells and CD4+ T cells.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Receptor de Muerte Celular Programada 1/metabolismo , Subgrupos de Linfocitos T/metabolismo , Adolescente , Adulto , Relación CD4-CD8 , Estudios de Casos y Controles , Femenino , Hepatitis C Crónica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Adulto JovenRESUMEN
Primary hepatic amyloidosis (PHA) is characterized by abnormal deposition of monoclonal immunoglobulin light chains (AL) in the liver. This rare condition is frequently undiagnosed or misdiagnosed and can be associated with poor prognosis. At present, the precise pathogenesis is not fully understood. Despite that hepatomegaly and elevated alkaline phosphatase (ALP) are present in most patients with PHA, no specific clinical markers have been identified. Staining of hepatic tissues with Congo Red is often regarded as the "gold standard". Pharmacological therapy should aim to rapidly reduce the supply of misfolded amyloidogenic AL. High-dose intravenous melphalan (HDM) and autologous stem cell transplantation (ASCT) appear to be the most appropriate therapy but controversies still exist.
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Amiloidosis , Hepatopatías , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Amiloidosis/epidemiología , Amiloidosis/inmunología , Amiloidosis/terapia , Biomarcadores/análisis , Diagnóstico Diferencial , Humanos , Cadenas Ligeras de Inmunoglobulina/análisis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Hígado/inmunología , Hígado/patología , Hepatopatías/complicaciones , Hepatopatías/diagnóstico , Hepatopatías/epidemiología , Hepatopatías/inmunología , Hepatopatías/terapia , Melfalán/administración & dosificación , Valor Predictivo de las Pruebas , Trasplante de Células Madre , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Monotherapy with pegylated interferon alpha (Peg-IFNa) or adefovir dipivoxil (ADV) to HBeAg-positive chronic hepatitis B (CHB) patients has limited effects. This study aims to evaluate therapeutic efficacy and safety of individualized combination therapy with Peg-IFNa and ADV. METHODOLOGY: HBeAg-positive CHB patients (n=160) were enrolled in this multi-center, prospective, randomized, 'real-life' cohort study, of which received Peg IFNa-2a monotherapy or combination therapy with ADV base on the baseline features and treatment response. RESULTS: At week 24, percentages of ALT normalization, HBV DNA undetectable were both higher in individualized treatment group (ITG, 57.50%, 43.75%) than that in standard treatment group (STG, 40.00%, 27.50%; p=0.027, 0.032). The superiority of HBeAg clearance and seroconversion rates in ITG maintained from treatment termination (63.75%, 56.25%) to 48 weeks follow-up (57.50%, 53.75%). At week 96 the combined response rates were 46.25% in ITG compared with 30.00% in STG (p=0.034). Furthermore, there was no statistically significant difference in relapse rates and adverse events between the two groups. CONCLUSIONS: Individualized combination therapy can achieve higher antiviral response rates. In particular, it can accelerate undetectable HBV DNA and elevate HBeAg clearance/seroconversion rates to a greater degree than Peg-IFNa-2a monotherapy.
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Adenina/análogos & derivados , Antivirales/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Organofosfonatos/uso terapéutico , Polietilenglicoles/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Biomarcadores/sangre , Distribución de Chi-Cuadrado , China , ADN Viral/sangre , Quimioterapia Combinada , Femenino , Virus de la Hepatitis B/genética , Hepatitis B Crónica/diagnóstico , Humanos , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Polietilenglicoles/efectos adversos , Medicina de Precisión , Estudios Prospectivos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore the effects of Xinganbao Capsule (Cordyceps Sinensis) on the chronic hepatitis B liver fibrosis. METHODS: Sixty patients with chronic hepatitis B were randomly assigned to the trail group (40 cases) and the control group (20 cases). The trail group was treated with Xinganbao Capsule, 8 capsules each time, three times a day. The control group was given Heluo Shugan Tablet, 5 pills each time, thrice daily. Six months consisted of one therapeutic course. The liver function, four indicators of serum fibrosis, liver histology, and other items were detected. RESULTS: Xinganbao Capsule could reduce serum ALT and AST levels, serum HA, PC-III and LN levels (all P<0.05), showing statistical difference when compared with before treatment. The HA and LN levels decreased more significantly in the control group when compared with before treatment (P<0.05). Totally 21 patients (53% of the recruited cases) in the trial group completed the liver biopsy twice. After treated with Xinganbao Capsule, 81% patients (17/21) had decreased liver inflammation 1 grade or more, 52% patients (11/21) had decreased fibrosis staging one or more, and 33% (7/21) patients had no change in fibrosis. CONCLUSION: Xinganbao Capsule could improve the liver function, reduce liver inflammation, and fight against hepatic fibrosis.
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Medicamentos Herbarios Chinos/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Fitoterapia , Adulto , Femenino , Hepatitis B Crónica/patología , Humanos , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the underlying molecular mechanism of the cholesterol-blocking drug, simvastatin, in treating nonalcoholic fatty liver fibrosis. METHOD: A rat model of nonalcoholic fatty liver fibrosis was established by feeding Wistar rats a fat-rich diet. After treatment with simvastatin (4 mg/kg/day), liver histological specimens were stained with hematoxylin-eosin and Masson's trichrome for microscopic analysis. Expression of adenosine monophosphate-activated protein kinase-alpha (AMPKa) was evaluated by reverse transcription-polymerase chain reaction (RT-PCR; for mRNA) and Western blotting (protein). The levels of serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor-alpha (TNFa) were measured by standard biochemical assays. The human hepatic stellate cell line, LX-2 (quiescent or activated), was treated with transforming growth factor-beta 1 (TGF-b1) alone, simvastatin alone, or TGF-b1 + simvastatin. RT-PCR and Western blotting were used to determine changes in AMPKa mRNA and protein expression, respectively. RESULTS: In the rat model of nonalcoholic fatty liver fibrosis, the extent of pathological changes in hepatic tissues correlated with severity of disease progression. The levels of serum TC, TG, ALT, AST and TNFa were increased significantly in model rats (vs. healthy controls; all, P less than 0.01). AMPKa mRNA expression and activity was significantly decreased in model rats (vs. healthy controls; P less than 0.01 and P less than 0.05, respectively). Simvastatin, treatment significantly improved all of these parameters in model rats (vs. untreated model rats; all, P less than 0.05). In vitro simvastatin treatment of human HSCs significantly increased AMPKa activity (quiescent LX-2: 0.93+/-0.10 vs. 0.72+/-0.09, activated LX-2: 0.72+/-0.10 vs. 0.54+/-0.10, q=7.00, 6.00; all, P less than 0.01), decreased a-smooth muscle actin expression (mRNA: 0.30+/-0.02 vs. 0.36+/-0.02, protein: 0.30+/-0.03 vs. 0.38+/-0.02, q=11.245, 11.216; all, P less than 0.01), and decreased collagen I expression (mRNA: 0.30+/-0.03 vs. 0.37+/-0.03, protein: 0.25+/-0.03 vs. 0.33+/-0.03, q=8.791, 11.163; all, P less than 0.01). CONCLUSION: Simvastatin may improve nonalcoholic fatty liver fibrosis by inducing AMPK phosphorylation.
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Adenilato Quinasa/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/enzimología , Simvastatina/farmacología , Animales , Línea Celular , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Hígado Graso/patología , Humanos , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratas , Ratas Wistar , Simvastatina/uso terapéuticoRESUMEN
OBJECTIVE: Based on the potential for nucleotide analogues to affect DNA polymerase-gamma, which controls the proliferation of mitochondria, this study aimed to determine whether long-term treatment with entecavir can cause damage to mitochondrial (mt)DNA in the peripheral blood mononuclear cells (PBMCs) of patients with chronic hepatitis B (CHB). METHODS: Patients with CHB were divided into three groups according to their history of treatment type and duration: (1) entecavir monotherapy for 2 years, n = 17; (2) entecavir monotherapy for 3 years, n = 17; (3) non-antiviral treatment as control, n = 18. PBMCs were isolated and used to assess the mtDNA content by quantitative real-time PCR of mitochondria-specific genes. Plasma malonaldehyde (MDA) and F2-isoprostanes were measured by enzyme linked immunosorbent assay. Plasma total antioxidant capacity (TAOC) was detected by spectrophotometry. RESULTS: The relative quantity (RQ; of mtDNA to nuclear (n)DNA) was significantly lower in the 3-year treatment group (0.5+/-0.3) than in the control group (1.4+/-1.2; F = 5.233, P = 0.009). The RQ was also significantly lower in the 2-year treatment group (0.4+/-0.2) than in the control group (P = 0.004). The level of F2-isoprostanes (ng/mL) was significantly lower in the 3-year treatment group (1.2+/-0.5) than in the control group (3.6+/-2.9, P = 0.002) or the 2-year treatment group (2.4+/-1.3, P = 0.007). The TAOC was significantly different when compared among all three groups (F = 4.326, P = 0.019). The TAOC (IU/mL) in the 3-year treatment group (2.6+/-1.2) was significantly lower than in the control group (5.0+/-3.0 P = 0.005), but was not significantly different than that for the 2-year group (3.2+/-1.6, P = 0.227). The levels of MDA were not significantly different between any of the groups (F = 0.291, P = 0.749). CONCLUSION: Long-term treatment with entecavir, up to 3 years, leads to decreased mtDNA content in PBMCs. Since no clinical manifestations of mtDNA toxicity were observed, the consequent damage to the mitochondrial function may be compensated for by yet unknown mechanisms.
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Antivirales/efectos adversos , Daño del ADN/efectos de los fármacos , ADN Mitocondrial/efectos de los fármacos , Guanina/análogos & derivados , Hepatitis B Crónica/sangre , Adulto , Femenino , Guanina/efectos adversos , Humanos , Leucocitos Mononucleares/citología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To investigate the role of endoplasmic reticulum stress (ERS) in alcoholic liver disease (ALD)-related hepatocyte apoptosis. METHODS: A rat model of ALD was established by continuous intragastric administration of ethanol. At 4, 8, 12, and 16 weeks later, randomly selected rats were sacrificed for serum and liver sample collection. Serum levels of total homocysteine (tHcy) were examined by chemiluminescence analysis. Cystathionine beta-synthase (CBS) activity in liver tissue was measured by chromatometry. The mRNA and protein expressions of ERS-related factors, glucose-regulated protein (GRP)-78, calpain 2 and caspase-12, were analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. Hepatocyte apoptosis was detected by the TdT-mediated dUTP nick end labeling assay. RESULTS: At 16 weeks, the ALD rats' livers exhibited diffuse microvesicular adipose degeneration and fibrosis in the liver sinus and portal septa. As the duration of ethanol administration extended, the tHcy levels gradually increased (P less than 0.01), CBS activity decreased (P less than 0.01), gene expression levels of GRP-78, calpain 2, and caspase-12 were up-regulated (P less than 0.01), and protein expression levels of GRP-78 and calpain 2 were gradually increased. However, the protein level of procaspase-12 was found to decrease with increased duration of ethanol administration. Finally, the hepatocyte apoptosis index showed an increasing trend over time (P less than 0.01). CONCLUSION: In our experimental ALD rat model, hepatic apoptosis was detected with increasing frequency over the duration of ALD. Increased apoptosis was likely due to decreased CBS activity causing hyperhomocysteinemia, which further induced ERS and activated the calpain 2 and caspase-12 signaling pathway. These ethanol-induced molecular changes may provoke hepatic apoptosis and subsequently promote the pathogenic processes of alcoholic liver disease.
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Apoptosis , Estrés del Retículo Endoplásmico , Hepatocitos/patología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Animales , Calpaína/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Hepatocitos/metabolismo , Hígado/patología , Masculino , Proteínas de la Membrana/metabolismo , Ratas , Ratas WistarRESUMEN
Tetrachloroethylene is a chlorinated solvent that is primarily used in dry cleaning and degreasing operations. Although the hepatotoxicity caused by tetrachloroethylene has been well documented in literature, it is rarely considered as a cause of acute liver failure. We report a case of a 39-yr-old man who was admitted to our hospital for acute liver failure due to tetrachloroethylene exposure. Histological examination of the liver revealed massive hepatic necrosis, prominently, in zone 3 of the hepatic lobules. The patient underwent supportive treatment along with 3 sessions of plasmapheresis, and consequently, he presented a favorable outcome. Repeat liver biopsy performed 6 months after the patient's discharge showed architectural distortion with postnecrotic cirrhosis. Physicians should be aware of the possibility of acute liver failure induced by tetrachloroethylene. Early plasmapheresis can be effective for individuals with sufficient capacity for hepatocyte regeneration.
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Carcinógenos/toxicidad , Fallo Hepático Agudo/diagnóstico , Exposición Profesional , Tetracloroetileno/toxicidad , Adulto , Humanos , Cirrosis Hepática/patología , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/patología , Masculino , PlasmaféresisRESUMEN
OBJECTIVE: To investigate the molecular mechanism of adiponectin inhibiting activation of hepatic stellate cells in non-alcoholic fatty liver fibrosis. METHODS: The rat models of non-alcoholic fatty liver fibrosis were successfully established by fat-rich diet administration. The expression of adiponectin mRNA and protein were respectively detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. LX-2 cells were cultured in an adipogenic differentiation mixture to induce quiescent adipocytic phenotypes, and then they were treated with TGFß1, adiponectin and TGFß1 + adiponectin, respectively. RT-PCR and Western blot were used to determine the expressions of mRNAs and proteins of a-smooth muscle actin (a-SMA), Collagen, adenosine monophosphate-activated protein kinase (AMPK), inducible nitric oxide synthase (iNOS), and endothelial NOS (eNOS). The results were analyzed using one-way ANOVA, Student-Newman-Keuls test, and linear correlation analysis. A P value of less than 0.05 was considered as statistically significant. RESULTS: In vivo, with the progress of non-alcoholic fatty liver fibrosis, the model rats gradually showed hepatic steatosis, inflammation, necrosis and fibrosis. Compared with the control group, the level of serum adiponectin (2.49 ± 0.86 vs 5.81 ± 0.87, P < 0.05) and hepatic expressions of adiponectin mRNA and protein (0.26 ± 0.04 vs 0.72 ± 0.08; 0.64 ± 0.07 vs 0.21 ± 0.07, all P < 0.05) were all decreased in the 24th week group, and were negatively correlated with the level of Collagen which increased gradually. In vitro, TGFß1 could activate quiescent LX-2 cells by decreasing mRNA and protein expression of eNOS (0.30 ± 0.10 vs 0.44 ± 0.08; 0.30 ± 0.09 vs 0.46 ± 0.07, all P < 0.05) and increasing the expression of iNOS (0.53 ± 0.07 vs 0.37 ± 0.04; 0.55 ± 0.07 vs 0.39 ± 0.05, all P < 0.05). Recombinant adiponectin not only maintained the quiescent phenotype of LX-2 cells but also inhibited LX-2 cells activation due to TGFß1 by increasing the expression of eNOS (0.43 ± 0.08 vs 0.30 ± 0.10; 0.42 ± 0.07 vs 0.30 ± 0.09, all P < 0.05) and phosphorylation of AMPK (0.43 ± 0.07 vs 0.24 ± 0.04, P < 0.05) and decreasing the expression of iNOS (0.44 ± 0.05 vs 0.53 ± 0.07; 0.46 ± 0.07 vs 0.55 ± 0.07, all P < 0.05). CONCLUSIONS: Data suggested that adiponectin could play a protective role on the pathogenesis of non-alcoholic fatty liver fibrosis by inhibiting the activation of hepatic stellate cells via up-regulating the expression of eNOS, which might associate with increased phosphorylation of AMPK.
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Adiponectina/metabolismo , Células Estrelladas Hepáticas/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Adiponectina/farmacología , Animales , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic disorders. This study aimed to explore the role of metabolic disorders in screening advanced fibrosis in NAFLD patients. METHODS: A total of 246 histologically-proven NAFLD patients were enrolled across 14 centers. We compared the severity of fibrosis in patients with different components of metabolic disorders. Based on standard noninvasive tests and metabolic disorders, we developed new algorithms to identify advanced fibrosis. RESULTS: Metabolic syndrome (MetS) was frequent in NAFLD patients (133/246, 54%). Patients with MetS had a higher proportion of significant fibrosis (p=0.014) and higher LSM values (9.2 kPa, vs. 7.4 kPa, p=0.002) than those without MetS. Patients with more metabolic disorders had higher fibrosis stages (p=0.017). Reduced high-density lipoprotein cholesterol (odds ratio [OR]: 2.241, 95% confidence interval [CI]: 1.004-5.002, p=0.049) and raised fasting glucose (OR: 4.500, 95% CI: 2.083-9.725, p<0.001) were significantly associated with advanced fibrosis. Using these two metabolic disorders as a screening tool, a sensitivity, specificity and accuracy of 92%, 81% and 83% was achieved, respectively. With the new algorithms combining metabolic disorders with noninvasive measurements, the number of patients requiring liver biopsy was reduced, especially in combination with the Fibrosis-4 score and metabolic disorders (36% to 17%, p<0.001). In addition, this stepwise algorithm could achieve a high accuracy (85%) and high negative predictive value (93%). CONCLUSIONS: Metabolic disorders should be taken into consideration in the diagnosis of advanced fibrosis. With further validation and investigation, new algorithms could be recommended in primary care units to spare patients from unnecessary referral and liver biopsies.
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BACKGROUND: Thiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases. CASE PRESENTATION: We described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation. CONCLUSIONS: This case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important.
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Antitiroideos/efectos adversos , Antitiroideos/uso terapéutico , Hipertiroidismo/tratamiento farmacológico , Fallo Hepático/inducido químicamente , Metimazol/efectos adversos , Metimazol/uso terapéutico , Trilogía de Fallot/complicaciones , Resultado Fatal , Humanos , Fallo Hepático/diagnóstico , Masculino , Adulto JovenRESUMEN
OBJECTIVE: To investigate the role and molecular mechanism of resistin in inflammation of hepatocytes in nonalcoholic steatohepatitis. METHODS: Rat models of NASH were established successfully. The expression of resistin mRNA and protein were examined by quantitative RT-PCR and immunohistolostaining, respectively. The murine hepatocytes AML-12 were incubated with recombinant resistin or LPS for 48 hours, and the concentration of TNF alpha, IL-6 in supernatant of AML-12 cells were quantified by enzyme linked immunosorbent assay (ELISA), the nuclear translocation NF- kappa B were observed by immunofluorescence. RESULTS: The steatosis of hepatocytes, inflammation in the lobule and perisinusoidal fibrosis in livers were found, and the expression of resistin mRNA and protein were increased in livers of rat model of NASH. The expression of resistin mRNA was 2.5 and 4 time higher in 12 weeks and 16 weeks of rat models respectively than that in normal control. The positive staining of resistin protein can be found mainly around the central veins. The concentration of TNF alpha and IL-6 were (1.856 +/- 0.049) pg/ml and (9.463 +/- 1.216) pg/ml in supernantant of AML-12 cells 48 hours after recombinant resistin treatment, and (1.791 +/- 0.046) pg/ml, (8.738 +/- 1.101) pg/ml 48 hours after LPS treatment. There was no significant difference between them, but both were higher than that in normal control (P < 0.01). The NF- kappa B p65 nuclear translocation had been observed in AML-12 cells 3 hours after resistin or LPS treatment. CONCLUSIONS: Resistin can induce the production of TNF alpha, IL-6 and other inflammatory factors by hepatocytes, and therefore is an important inflammatory factor in NASH.
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Hígado Graso/etiología , Mediadores de Inflamación/metabolismo , Inflamación/etiología , Hígado/metabolismo , Resistina/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Hígado Graso/metabolismo , Inmunohistoquímica , Inflamación/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , FN-kappa B/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Resistina/genética , Resistina/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Recent advance in the direct-acting antivirals (DAAs) offers the potentials to eradicate hepatitis C virus (HCV) worldwide and makes universal screening more urgent. A point-of-care (POC) oral anti-HCV assay, the Fortune assay, was developed and its performance was evaluated. Individuals with or without HCV infection were recruited in three Centers. Paired oral and serum samples were tested using the Fortune and InTec anti-HCV assays. The Kehua serum anti-HCV assay served as a supplemental test to verify the discordant results. Some oral samples were also tested using the OraQuick anti-HCV assay. Furthermore, the Fortune assay results were compared with the documented RNA results. Sensitivity, specificity, and accuracy of the Fortune assay was 93.11%, 98.48%, and 96.58%, respectively (n = 1,022). Consistency between the Fortune and OraQuick assays was 96.35% (264/274); the Fortune assay detected additional 8 positive oral samples missed by the OraQuick assay. The Fortune assay demonstrated a 97.46% (115/118) positivity among the viremic patients. Furthermore, its sensitivity was HCV genotype independent. In conclusion, the Fortune assay was highly specific and accurate. It had comparable sensitivity as the serum assays for the diagnosis of active HCV infection. It provides a completely non-invasive and reliable tool for HCV screening in the DAA era.
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Genotipo , Hepacivirus/genética , Hepatitis C/sangre , Hepatitis C/genética , Sistemas de Atención de Punto , ARN Viral , Adulto , Antivirales/uso terapéutico , Femenino , Hepatitis C/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , ARN Viral/genética , Sensibilidad y EspecificidadRESUMEN
RATIONALE: Chronic active Epstein-Barr virus infection (CAEBV) is a common infectious disease that often affects multiple organs or systems. However, it is liable to be neglected and misdiagnosed owing to its insidious onset, lack of specific findings in the early phase, and a general lack of awareness among clinicians. PATIENT CONCERNS:: a 27-year-old woman case has been described who was initially misdiagnosed as drug-induced liver injury due to onset presentation of mild splenomegaly, recurrent liver dysfunction, and disputable pathological evidence of liver biopsy. DIAGNOSES: CAEBV complicated with natural killer (NK) cell lymphoma and hemophagocytic lymphohistiocytosis (HLH) was diagnosed by in situ hybridization of liver tissue section with EBV-encoded RNA -1 probe and flow cytometry of bone marrow. INTERVENTIONS: After admission, the patient received symptomatic treatment and antiviral therapy (combination of acyclovir and foscarnet sodium) as well as adjuvant treatment (thymosin alpha 1 and methylprednisolone); later, the patient received etoposide and dexamethasone for diagnosis of EBV associated HLH. Subsequently, the disease progressed to NK cell lymphoma and the patient received the revised EPOCH chemotherapy regimen [etoposide (100âmg/d, d1-5), dexamethasone (7.5âmg/d, d1-5; 5âmg/d, d6-14), cyclophosphamide (0.8âg/d, d1-2), and pegaspargase (3750âu/d, tid, d1-2)]. OUTCOMES: Although the patient received a series of therapies and other comprehensive measures, finally she died of gastrointestinal hemorrhage and multiple organ failure. LESSONS: Liver is one of the main target organs of EBV infection. In the clinical setting of unexplained fever and liver injury, it is necessary to be aware of CAEBV, as well as its fatal complication such as EBV associated NK cell lymphoma and HLH.