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1.
Gut ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431576

RESUMO

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

2.
Sci Rep ; 11(1): 1810, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469110

RESUMO

Acute-on-chronic liver failure (ACLF) is a dynamic syndrome, and sequential assessments can reflect its prognosis more accurately. Our aim was to build and validate a new scoring system to predict short-term prognosis using baseline and dynamic data in ACLF. We conducted a retrospective cohort analysis of patients with ACLF from three different hospitals in China. To construct the model, we analyzed a training set of 541 patients from two hospitals. The model's performance was evaluated in a validation set of 130 patients from another center. In the training set, multivariate Cox regression analysis revealed that age, WGO type, basic etiology, total bilirubin, creatinine, prothrombin activity, and hepatic encephalopathy stage were all independent prognostic factors in ACLF. We designed a dynamic trend score table based on the changing trends of these indicators. Furthermore, a logistic prediction model (DP-ACLF) was constructed by combining the sum of dynamic trend scores and baseline prognostic parameters. All prognostic scores were calculated based on the clinical data of patients at the third day, first week, and second week after admission, respectively, and were correlated with the 90-day prognosis by ROC analysis. Comparative analysis showed that the AUC value for DP-ACLF was higher than for other prognostic scores, including Child-Turcotte-Pugh, MELD, MELD-Na, CLIF-SOFA, CLIF-C ACLF, and COSSH-ACLF. The new scoring model, which combined baseline characteristics and dynamic changes in clinical indicators to predict the course of ACLF, showed a better prognostic ability than current scoring systems. Prospective studies are needed to validate these results.

3.
Sci Rep ; 10(1): 20176, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214662

RESUMO

We aimed to develop a prediction model based on the PIRO concept (Predisposition, Injury, Response and Organ failure) for patients with Hepatitis B Virus (HBV) related acute-on-chronic liver failure (ACLF). 774 patients with HBV related ACLF defined in the CANONIC study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification and regression tree was used to stratify patients into different nodes. The prediction model was then validated using an independent cohort (n = 155). Factors significantly associated with 90-day mortality were: P: age, gender and ACLF type; I: drug, infection, surgery, and variceal bleeding; R: systemic inflammatory response syndrome (SIRS), spontaneous bacteria peritonitis (SBP), and pneumonia; and O: the CLIF consortium organ failure score (CLIF-C OFs). The areas under the receiver operating characteristics curve (95% confidence interval) for the combined PIRO model for 90-day mortality were 0.77 (0.73-0.80). Based on the scores for each of the PIRO components and the cut-offs estimated from the classification and regression tree, patients were stratified into different nodes with different estimated death probability. Based on the PIRO concept, a new prediction model was developed for patients with HBV related ACLF, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed model will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes.

4.
Braz J Med Biol Res ; 53(11): e9728, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33053116

RESUMO

The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada , Vírus da Hepatite B , Hepatite B/complicações , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/terapia , Adulto , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Transplante de Células-Tronco
5.
Hepatol Res ; 50(6): 656-670, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32134538

RESUMO

AIM: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. However, patient survival remains unknown. We aim to assess the effects of ALSS on survival in HBV-ACLF patients. METHODS: The clinical data of HBV-ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment. The main end-points were cumulative survival rates at days 21, 28, and 90. Four different rigorous analyses were carried out to reduce bias and confounding. RESULTS: In the entire cohort, the cumulative survival rates at days 21, 28, and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P < 0.01) than in those who underwent SMT only. In the 276-pair case-control matched cohort, a significantly higher survival rate was also observed in the ALSS group than in the SMT group on days 21, 28, and 90 (72.5% vs. 60.3%, 68.3% vs. 57.4%, 55.9% vs. 48.5%, respectively, P < 0.05), especially in patients with ACLF-1 and -2. By a multivariable-adjusted analysis, ALSS treatment was associated with a significantly lower risk of mortality, especially for ACLF-2 at days 21, 28, and 90. These findings were also confirmed through propensity score matching and inverse probability treatment weighting analysis. CONCLUSIONS: ALSS treatment can improve short-term survival and is associated with a significantly lower risk of short-term mortality in patients with HBV-ACLF, especially ACLF-2.

6.
J Nanosci Nanotechnol ; 20(3): 1530-1539, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492316

RESUMO

In this work, we study the indentation deformation of a Cu47.5Zr19Hf28.5Al5 bulk-metallic glass-matrix composite and characterize the effects of the indentation-loading rate and the holding time at the peak-indentation load. For the same peak-indentation load, increasing the holding time and/or decreasing the indentation-loading rate cause the increase of the indentation depth. There exists the "bulge" of the unloading curve at the onset of the unloading for small indentation-loading rates. The Vickers hardness is a monotonically increasing function of the indentation-loading rate for the same peak-indentation load. For the indentations with the same loading and unloading time of 30 s and without an intermediate stage at the peak-indentation load, the Vickers hardness of the Cu47.5Zr19Hf28.5Al5 bulk-metallic glass-matrix composite decreases with the increase of the indentation load. The strain energy dissipated through plastic deformation during the indentation is a power-law function of the indentation load with a power index of 3/2, and the energy ratio (total energy/plastic energy) linearly increases with the depth ratio (residual indentation depth/maximum indentation depth).

7.
Braz. j. med. biol. res ; 53(11): e9728, 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS, Coleciona SUS | ID: biblio-1132496

RESUMO

The aim of this study was to propose a stem cell therapy for hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) based on plasma exchange (PE) for peripheral blood stem cell (PBSC) collection and examine its safety and efficacy. Sixty patients (n=20 in each group) were randomized to PE (PE alone), granulocyte colony-stimulating factor (G-CSF) (PE after G-CSF treatment), and PBSC transplantation (PBSCT) (G-CSF, PE, PBSC collection and hepatic artery injection) groups. Patients were followed-up for 24 weeks. Liver function and adverse events were recorded. Survival analysis was performed. PBSCT improved blood ammonia levels at 1 week (P<0.05). The level of total bilirubin, international normalized ratio, and creatinine showed significant differences in the 4th week of treatment (P<0.05). The survival rates of the PE, G-CSF, and PBSCT groups were 50, 65, and 85% at 90 days (P=0.034). There was a significant difference in 90-day survival between the PE and PBSCT groups (P=0.021). The preliminary results suggested that PBSCT was safe, with a possibility of improved 90-day survival in patients with HBV-ACLF.

8.
Hepatol Int ; 13(6): 695-705, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31650510

RESUMO

BACKGROUND AND AIM: Cirrhosis is a controversial determinant of mortality in HBV-related acute-on-chronic liver failure (HBV-ACLF). The present study aimed to explore the effects of cirrhosis and the associated risk factors, especially its complications, on the outcome of HBV-ACLF. METHODS: A prospective-retrospective cohort of 985 patients was identified from the APASL-ACLF Research Consortium (AARC) database and the Chinese Study Group. Complications of ACLF (ascites, infection, hepatorenal syndrome, hepatic encephalopathy, upper gastrointestinal bleeding) as well as cirrhosis and the current main prognostic models were measured for their predictive ability for 28- or 90-day mortality. RESULTS: A total of 709 patients with HBV-ACLF as defined by the AARC criteria were enrolled. Among these HBV-ACLF patients, the cirrhotic group showed significantly higher mortality and complications than the non-cirrhotic group. A total of 36.1% and 40.1% of patients met the European Association for the Study of Liver (EASL)-Chronic Liver Failure consortium (CLIF-C) criteria in the non-cirrhotic and cirrhotic groups, respectively; these patients had significantly higher rates of mortality and complications than those who did not satisfy the CLIF-C criteria. Furthermore, among patients who did not meet the CLIF-C criteria, the cirrhotic group exhibited higher mortality and complication rates than the non-cirrhotic group, without significant differences in organ failure. The Tongji prognostic predictor model score (TPPMs), which set the number of complications as one of the determinants, showed comparable or superior ability to the Chinese Group on the Study of Severe Hepatitis B-ACLF score (COSSH-ACLFs), APASL-ACLF Research Consortium score (AARC-ACLFs), CLIF-C organ failure score (CLIF-C OFs), CLIF-C-ACLF score (CLIF-C-ACLFs), Model for End-Stage Liver Disease score (MELDs) and MELD-sodium score (MELD-Nas) in HBV-ACLF patients, especially in cirrhotic HBV--ACLF patients. Patients with two (OR 4.70, 1.88) or three (OR 8.27, 2.65) complications had a significantly higher risk of 28- or 90-day mortality, respectively. CONCLUSION: The presence of complications is a major risk factor for mortality in HBV-ACLF patients. TPPM possesses high predictive ability in HBV-ACLF patients, especially in cirrhotic HBV-ACLF patients.


Assuntos
Insuficiência Hepática Crônica Agudizada/epidemiologia , Vírus da Hepatite B , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/virologia , Adulto , Ascite/complicações , Ásia/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
9.
Medicine (Baltimore) ; 98(1): e13983, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608440

RESUMO

OBJECTIVE: We conducted this study to compare the efficacy and safety of entecavir and tenofovir in the treatment of treatment-naïve HBV e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) for 144 weeks. METHODS: A total of 320 treatment-naïve HBeAg-positive CHB patients who received randomly a single regimen of either entecavir capsule (ETV) (n = 160) or tenofovir disoproxil fumarate capsule (TDF) (n = 160) for 144 weeks were consecutively enrolled from 14 tertiary hospitals or university hospitals in China between January 2012 and December 2014. RESULTS: Two groups showed no difference in baseline characteristics. After 144 weeks of treatment, HBV DNA levels were similarly suppressed in both groups (ETV vs TDF; -6.6485 vs -6.692 log10IU/mL, P = .807). At the same time, both groups showed no difference in terms of the serologic and biochemical response. Of all patients, 2 dropped out due to adverse events and 5 experienced serious adverse reactions. CONCLUSION: Both capsules (ETV or TDF) were equally effective in nucleos(t)ide-naive CHB patients with a comparable side-effect profile even in a long-term of 144 weeks.


Assuntos
Guanina/análogos & derivados , Antígenos E da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Adulto , Antivirais/efeitos adversos , Antivirais/uso terapêutico , China/epidemiologia , DNA Viral/efeitos dos fármacos , Feminino , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Humanos , Masculino , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Resultado do Tratamento
10.
Hepat Med ; 10: 139-152, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532603

RESUMO

Background: Preliminary evidence of safety and efficacy of an extracorporeal cellular therapy (ELAD®) has been demonstrated in subjects with acute forms of liver failure. This study compared ELAD with standard of care in Chinese subjects with acute-on-chronic liver failure (ACLF), predominantly secondary to chronic viral hepatitis. Subjects and methods: Subjects meeting eligibility criteria were randomized to either the ELAD group or the control group. All subjects received plasma exchange and venovenous hemofiltration and either ELAD treatment for 3-5 days, unless terminated early, along with standard of care or standard of care alone (control) and were then followed up for 12 weeks. Results: Forty-nine subjects (ELAD subjects, 32; controls, 17) were randomized under this protocol. Kaplan-Meier analysis of transplant-free survival (TFS) revealed a significant difference in favor of ELAD vs control (P=0.049, Wilcoxon signed-rank test). There was a significant difference in TFS on day 28 in ELAD vs control (P=0.022). In a multiple regression model, the relationship between group assignment and outcome was significant (P=0.031) when changes in food intake and Model for End-Stage Liver Disease (MELD) scores at screening were included as additional independent variables. The duration of ELAD treatment alone was a significant predictor of TFS (P=0.043). Median time to a 5-point increase in MELD, transplant, or death was longer than 72 days with ELAD vs 26 days for control (P=0.036). Total bilirubin level decreased by 25% during ELAD treatment vs 37% increase in the control group (P<0.001) over an equivalent period. Adverse events attributed to the ELAD system were expected and could be managed conservatively. Intergroup differences in certain vital signs and laboratory parameters were noted during treatment and generally resolved posttreatment. Conclusion: ELAD treatment was well tolerated by Chinese subjects with ACLF, predominately secondary to chronic viral hepatitis. Results demonstrate a significant improvement in TFS in ELAD vs control groups in association with significant improvements in serum bilirubin levels presumably related to improvement in hepatic function.

11.
Medicine (Baltimore) ; 97(34): e11915, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142800

RESUMO

This study aimed to establish a new model for predicting acute-on-chronic liver failure (ACLF) (defined by the Chinese Medical Association), which potentially occurs among patients with acute deterioration (AD) of hepatitis B virus (HBV)-related chronic liver disease (CLD).A total of 754 patients with AD of HBV-related CLD (total bilirubin (TBIL) > 51.3 µmol/L and prothrombin activity (PTA) < 60%, 40% < PTA < 60% when TBIL ≥ 171.1 µmol/L) were retrospectively analyzed and divided into a training cohort (580 patients) and a validation cohort (174 patients). The ACLF occurrence probability of these patients was statistically analyzed within 4 weeks. In the training cohort, multivariate logistic regression analysis was performed to determine the independent predictors of ACLF occurrence and to develop a new prediction model. The validation cohort was utilized to verify and evaluate the value of the new prediction model.Within 4 weeks, 9.9% of the patients progressed to ACLF (12.0 ±â€Š6.7 days). The new prediction model was characterized by R = 3.090 + 0.035 × Age (years) - 0.050 × PTA (%) + 0.005 × TBIL (µmol/L) + 0.044 × D/T (%) - 0.072 × Na (mmol/L) + 0.180 × HBV DNA (log10IU/mL). The areas under the receiver operating characteristic curves of the training and validation cohorts in the new model were higher than those in the model for end-stage liver disease.The new prediction model could be used by clinicians to recognize patients with AD of HBV-related CLD with high risks of progressing to ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada/metabolismo , Hepatite B Crônica/complicações , Hepatite B Crônica/metabolismo , Insuficiência Hepática Crônica Agudizada/etiologia , Adulto , Área Sob a Curva , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Curva ROC , Estudos Retrospectivos
12.
Scand J Gastroenterol ; 53(3): 319-328, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29322851

RESUMO

OBJECTIVE: Mutations occurring within different genes of hepatitis B virus (HBV) genome may have different clinical implications. This study aimed to observe the clinical and virological implications of the A1846T and C1913A/G mutations of HBV genome in the development and treatment outcome of severe liver diseases, which has not been previously determined. MATERIALS AND METHODS: A total of 438 cases of patients with liver diseases were retrospectively reviewed, including 146 with mild chronic hepatitis B infection (CHB-M), 146 with severe chronic hepatitis B infection (CHB-S), and 146 with acute-on-chronic liver failure (ACLF). Partial or full-length HBV genome was directly sequenced. Replicons containing A1846T, C1913A or other mutant sequences, or the wild-type counterparts were constructed respectively, and then transfected into HepG2 cells for phenotype analysis. RESULTS: There was significant difference in the detection rates of A1846T (30.82%, 40.41% and 55.48%, respectively) and C1913A/G (15.52%, 28.77%, and 35.62%, respectively) among patients with CHB-M, those with CHB-S, and those with ACLF (p < .01). A1846T was significantly associated with the mortality of ACLF patients within six months after the disease onset (OR 1.704, p = .041). In vitro experiment revealed that A1846T mutant resulted in 3.20-fold and 1.85-fold increase of replication capacity and promoter activity, respectively compared with wild type counterpart (p < .001), while C1913A led to a significant decrease of core protein expression (p < .05). CONCLUSION: Occurrence of A1846T and C1913A is positively associated with clinical presentations of severe liver disease. A1846T mutation is significantly associated with poor prognosis of ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Genoma Viral , Vírus da Hepatite B/genética , Hepatite B Crônica/mortalidade , Insuficiência Hepática Crônica Agudizada/virologia , Adulto , Pequim/epidemiologia , DNA Viral/sangue , Feminino , Genótipo , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/virologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Estudos Retrospectivos
13.
Biochim Biophys Acta Gen Subj ; 1862(4): 1017-1030, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29369785

RESUMO

BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied. RESULTS: In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment. CONCLUSION: This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment. GENERAL SIGNIFICANCE: PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Receptores de Esteroides/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos SCID , Niacinamida/metabolismo , Niacinamida/uso terapêutico , Compostos de Fenilureia/metabolismo , Receptor de Pregnano X , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Interferência de RNA , Receptores de Esteroides/metabolismo , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
14.
Gut ; 67(12): 2181-2191, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28928275

RESUMO

OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.


Assuntos
Insuficiência Hepática Crônica Agudizada/diagnóstico , Hepatite B Crônica/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/microbiologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Adulto , Bilirrubina/sangue , Biomarcadores/sangue , China/epidemiologia , Feminino , Hepatite B Crônica/mortalidade , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
15.
Int J Clin Exp Pathol ; 10(11): 10781-10791, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-31966421

RESUMO

Liver failure is a life-threatened serious disease with many complications and high mortality rate. Stem cells have been applied to replacement therapy, gene therapy and tissue engineering for its capacity of self-renewal and multi-lineage differentiation. To investigate the bioactivity of the peripheral blood hematopoietic stem cells (PBHSC) in patients with acute-on-chronic liver failure, we isolated CD34+ cells from peripheral blood of patients with acute-on-chronic liver failure and healthy controls. After cultured it in serum-free medium (SFEM), we studied the bioactivity of CD34+ cells by observing the morphology, recording growth curve, detecting cell cycle and cell apoptosis. CD34+ cells and culture solution were collected at the time points of 3, 5, 7, 10, 12 and 14 days, and the levels of hepatocyte growth factor (HGF), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in culture solution were detected by ELISA. Also, the expressions of pyruvate kinase muscle isoenzyme 2 (PKM2), integrin-ß1 and liver-type pyruvate kinase (LPK) were detected by RT-PCR and immunofluorescence. Our results showed the bioactivity of CD34+ cells from patients with acute-on-chronic liver failure was identified to be similar with that from healthy controls. HGF, MMP-9, TNF-α and IL-6 were found in cell culture medium. RT-PCR and immunofluorescence results indicated that PKM2, Integrin-ß1 expressed on CD34+ cells from patients with acute-on-chronic liver failure. In conclusion, bioactivity of CD34+ cells of patients with acute-on-chronic liver failure was demonstrated to be normal, which could secrete HGF, MMP-9, TNF-α and IL-6, promote the growth of hepatocytes, and differentiate along a direction to hepatocyte lineage.

16.
Microb Drug Resist ; 23(4): 516-522, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27792585

RESUMO

The study aimed to investigate the association of prevalent genotypes in China (HBV/C and HBV/B) with HBV drug-resistant mutations. A total of 13,847 nucleos(t)ide analogue (NA)-treated patients with chronic HBV infection from North China were enrolled. HBV genotypes and resistant mutations were determined by direct sequencing and confirmed by clonal sequencing if necessary. HBV/B, HBV/C, and HBV/D occupied 14.3%, 84.9%, and 0.8% across the study population, respectively. NA usage had no significant difference between HBV/B- and HBV/C-infected patients. Lamivudine-resistant mutations were more frequently detected in HBV/C-infected patients, compared with HBV/B-infected patients (31.67% vs. 25.26%, p < 0.01). Adefovir- and entecavir-resistant mutation detection rates were similar, but the mutational pattern was different between the two genotypes. For adefovir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtA181 V (HBV/C 5.29% vs. HBV/B 1.36%, p < 0.01) and a lower detection rate of rtN236T (2.70% vs. 6.54%, p < 0.01). For entecavir-resistant mutations, HBV/C-infected patients had a higher detection rate of rtM204 V/I+T184 substitution or S202G/C (3.66% vs. 2.16%, p < 0.01) and a lower detection rate of rtM204 V/I+M250 V/I/L substitution (0.67% vs. 1.46%, p < 0.01). Multidrug-resistant mutations (defined as coexistence of mutation to nucleoside and nucleotide analogues) were detected in 104 patients. HBV/C-infected patients had a higher detection rate of multidrug-resistant mutation than HBV/B-infected patients (0.83% vs. 0.35%, p < 0.05). The study for the first time clarified that HBV/C-infected patients had a higher risk to develop multidrug-resistant mutations, compared with HBV/B-infected patients; and HBV/C- and HBV/B-infected patients had different inclinations in the ETV-resistant mutational pattern.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral Múltipla/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Taxa de Mutação , Proteínas Virais/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , China , Estudos de Coortes , Feminino , Expressão Gênica , Genótipo , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/classificação , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Lamivudina/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Filogenia
17.
Adv Exp Med Biol ; 948: 175-189, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27738985

RESUMO

The clinical manifestations of hepatitis E are similar to those of other types of viral hepatitis. While acute hepatitis E is usually self-limited, pregnant women and chronic liver disease patients suffering from acute hepatitis E usually present with severe clinical manifestations that may develop into fulminant hepatic failure. Chronic HEV infection is typically only seen in organ transplant patients; most HEV cases are asymptomatic and rarely display jaundice, fatigue, abdominal pain, fever, fatigue, or ascites. The clinical manifestations of HEV infection in neonates are diverse and have varied clinical signs, biochemistry, and virus biomarkers. Lastly, the extrahepatic manifestations and complications of hepatitis E are in need of further study.


Assuntos
Vírus da Hepatite E/fisiologia , Hepatite E/virologia , Feminino , Hepatite E/complicações , Vírus da Hepatite E/genética , Vírus da Hepatite E/isolamento & purificação , Humanos , Falência Hepática Aguda/etiologia , Masculino , Gravidez , Complicações Infecciosas na Gravidez/virologia
18.
Hepatol Int ; 10(5): 807-18, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27485174

RESUMO

BACKGROUND AND AIMS: Acute kidney injury (AKI) is a life-threatening complication in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis. However, the characteristics of AKI in these patients have not been clarified. Our aim was to determine the incidence and risk factors of AKI and the association between AKI severity and 180-day transplant-free survival. METHODS: We performed a retrospective cohort analysis of patients with ACLF of underlying cirrhosis in a single center from January 2009 through December 2014. AKI was defined by the criteria proposed by International Club of Ascites (ICA). The incidence and risk factors of AKI development and its relationship to 180-day transplant-free survival rates were evaluated. RESULTS: Of 1032 patients with ACLF of underlying cirrhosis, 121 (11.72 %) had AKI at admission, and 319 (30.9 %) developed AKI during hospitalization. We established a logistic regression model including four independent factors with AKI development: MELD score [odds ratio (OR), 1.1; 95 % confidence interval (CI), 1.07-1.14], presence of ascites (OR, 3.80; 95 % CI, 2.13-6.78), sepsis/infection (OR, 2.25; 95 % CI, 1.66-3.03) and acute variceal bleed (OR, 1.78; 95 % CI, 1.00-3.19). The area under receiver operating characteristics of the model in internal and external validations were 0.95 and 0.85, respectively. Patients with mild-A AKI had a higher 180-day transplant-free survival rate (23.8 %) than patients with mild-B AKI (19.0 %) or marked AKI (5.9 %) (all p < 0.001). AKI patients with a peak value of sCr <1.5 mg/dl had higher 180-day transplant-free survival rates compared to those with a peak value of sCr ≧1.5 mg/dl (23.8 % vs. 14.7 %, p < 0.001). CONCLUSIONS: We developed a clinical risk model for predicting development of AKI with great accuracy. Combining the ICA-AKI criteria and the peak value of sCr with 1.5 mg/dl provides a good prognostic method for patients with ACLF of underlying cirrhosis.


Assuntos
Lesão Renal Aguda/epidemiologia , Insuficiência Hepática Crônica Agudizada/epidemiologia , Cirrose Hepática/epidemiologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/mortalidade , Insuficiência Hepática Crônica Agudizada/complicações , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Transplante de Rim/estatística & dados numéricos , Cirrose Hepática/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida
19.
Cell Biochem Funct ; 34(7): 475-482, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27569862

RESUMO

The aim of this study was to investigate the differentiation potential of induced pluripotent stem cells (iPSCs) derived from human foreskin fibroblasts (HFFs) into hepatocyte-like cells (HLCs). The iPSCs were firstly induced by transduction of OCT4, SOX2, KLF4, and c-MYC into HFFs using retrovirus. Afterwards, expressions of pluripotency factors were identified by semiquantitative reverse transcription-polymerase chain reaction and immunofluorescence staining, and karyotype, embryoid, and teratoma were observed by microscope. Then, iPSCs were gradually differentiated into endoderm cells, hepatic progenitor cells, and mature HLCs by special culture medium. During this process, differentiation efficiency into each kind of cells was evaluated by detecting SOX17, HNF4a, and ALB using flow cytometry, respectively. Besides, enzyme-linked immunosorbent assay was conducted to detect the secretion of ALB in iPSC-induced HLCs and quantitative reverse transcription-polymerase chain reaction was performed to detect the expression levels of hepatocyte-specific genes. The iPSCs were successfully induced by HFFs, which exhibited typical embryonic stem cells morphology, positive alkaline phosphatase staining, normal diploid karyotype, and positive expression of various pluripotency factors. Meanwhile, spherical embryoid and teratoma with 3 germ layers were formed by iPSCs. The iPSCs were consecutively induced into endoderm cells, hepatic progenitor cells and mature HLCs, and the differentiation efficiency was 55.7 ± 2.9%, 45.7 ± 4.8%, and 35.0 ± 3.9%, respectively. Besides, the secretion of ALB and expression of various hepatocyte-specific genes was highly detected in iPSC-induced HLCs. The iPSCs were successfully derived from HFFs and then differentiated into HLCs, which proved a new source for hepatocyte transplantation. HIGHLIGHTS: HFFs were successfully induced into iPSCs by transduction of OCT4, SOX2, KLF4, and c-MYC. Positive expressions of various pluripotency factors were exhibited in HFFs-induced iPSCs. The iPSCs were consecutively induced into endoderm cells, hepatic progenitor cells, and mature HLCs. Various hepatocyte-specific genes were highly expressed in iPSC-induced HLCs.


Assuntos
Diferenciação Celular , Fibroblastos/citologia , Prepúcio do Pênis/citologia , Hepatócitos/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Albuminas/metabolismo , Corpos Embrioides/citologia , Fibroblastos/metabolismo , Imunofluorescência , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Cariotipagem , Masculino
20.
Med Sci Monit ; 22: 1817-26, 2016 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-27237628

RESUMO

BACKGROUND We aimed to evaluate the combination therapy of Chinese herbs plus interferon and ribavirin in treatment of patients with chronic hepatitis C (CHC). MATERIAL AND METHODS Related databases were searched to identify randomized controlled trials (RCTs) that evaluated biochemical response, virological response, histological response, and/or adverse reactions to combination therapy of interferon and ribavirin with and without Chinese herbs. The RR (relative risk) with a 95% confidence interval (CI) was calculated. Sensitivity analysis was conducted by omitting one study at a time. Publication bias among the eligible studies was evaluated by Egger's test. RESULTS A total of 17 RCTs matched the selection criteria. Overall, combination therapies of Chinese herbs plus interferon and ribavirin achieved significantly higher ALT (alanine transaminase) and ETVR (the end-of-treatment viral response), and significantly lower levels of HA (hyaluronic acid), LN (laminin), PC III (procollagen iii peptide), IV-C (type IV collagen), decreased LC (decreasing leukocyte count), ATF (abnormal thyroid function), psychosis, and anemia in CHC patients compared with those treated without Chinese herbs. Sensitivity analysis showed no changes and no potential publication bias was found. CONCLUSIONS The current evidence suggests that combination therapy of Chinese herb plus interferon and ribavirin yields better outcome and fewer adverse events in CHC patients than that of interferon plus ribavirin therapy.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferons/uso terapêutico , Ribavirina/uso terapêutico , Antivirais/uso terapêutico , Doença Crônica , Terapias Complementares/métodos , Quimioterapia Combinada , Humanos , Medicina Tradicional Chinesa , Resultado do Tratamento
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