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BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARα nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-ß-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARα nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARα nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.
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Falência Hepática Aguda , Células-Tronco , Tretinoína , Humanos , Tretinoína/farmacologia , Células-Tronco/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Técnicas de Cocultura , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismoRESUMO
Background and Aims: The role of platelet autophagy in cirrhotic thrombocytopenia (CTP) remains unclear. This study aimed to investigate the impact of platelet autophagy in CTP and elucidate the regulatory mechanism of hydrogen sulfide (H2S) on platelet autophagy. Methods: Platelets from 56 cirrhotic patients and 56 healthy individuals were isolated for in vitro analyses. Autophagy markers (ATG7, BECN1, LC3, and SQSTM1) were quantified using enzyme-linked immunosorbent assay, while autophagosomes were visualized through electron microscopy. Western blotting was used to assess the autophagy-related proteins and the PDGFR/PI3K/Akt/mTOR pathway following treatment with NaHS (an H2S donor), hydroxocobalamin (an H2S scavenger), or AG 1295 (a selective PDGFR-α inhibitor). A carbon tetrachloride-induced cirrhotic BALB/c mouse model was established. Cirrhotic mice with thrombocytopenia were randomly treated with normal saline, NaHS, or hydroxocobalamin for 15 days. Changes in platelet count and aggregation rate were observed every three days. Results: Cirrhotic patients with thrombocytopenia exhibited significantly decreased platelet autophagy markers and endogenous H2S levels, alongside increased platelet aggregation, compared to healthy controls. In vitro, NaHS treatment of platelets from severe CTP patients elevated LC3-II levels, reduced SQSTM1 levels, and decreased platelet aggregation in a dose-dependent manner. H2S treatment inhibited PDGFR, PI3K, Akt, and mTOR phosphorylation. In vivo, NaHS significantly increased LC3-II and decreased SQSTM1 expressions in platelets of cirrhotic mice, reducing platelet aggregation without affecting the platelet count. Conclusions: Diminished platelet autophagy potentially contributes to thrombocytopenia in cirrhotic patients. H2S modulates platelet autophagy and functions possibly via the PDGFR-α/PI3K/Akt/mTOR signaling pathway.
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In 2023, Chinese Society of Hepatology of Chinese Medical Association convened a panel of experts to update the Chinese guidelines on the management of ascites and associated complications in cirrhosis which was launched in 2017 and renamed this guidelines as "Guidelines on the Management of Ascites in Cirrhosis." This comprehensive resource offers essential recommendations for the diagnosis and treatment of cirrhotic ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome.
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Ascite , Síndrome Hepatorrenal , Cirrose Hepática , Humanos , Cirrose Hepática/complicações , Ascite/terapia , Ascite/etiologia , Ascite/diagnóstico , China , Síndrome Hepatorrenal/terapia , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/diagnóstico , Peritonite/terapia , Peritonite/diagnóstico , Peritonite/etiologia , Sociedades Médicas , Gastroenterologia/normasRESUMO
BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.
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Colangite Esclerosante , Registros Eletrônicos de Saúde , Humanos , Colangite Esclerosante/epidemiologia , China/epidemiologia , Prevalência , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Adolescente , Idoso , Doenças Inflamatórias Intestinais/epidemiologia , Adulto Jovem , CriançaRESUMO
Data on emergency endoscopic treatment following endotracheal intubation in patients with esophagogastric variceal bleeding (EGVB) remain limited. This retrospective study aimed to explore the efficacy and risk factors of bedside emergency endoscopic treatment following endotracheal intubation in severe EGVB patients admitted in Intensive Care Unit. A total of 165 EGVB patients were enrolled and allocated to training and validation sets in a randomly stratified manner. Univariate and multivariate logistic regression analyses were used to identify independent risk factors to construct nomograms for predicting the prognosis related to endoscopic hemostasis failure rate and 6-week mortality. In result, white blood cell counts (p = 0.03), Child-Turcotte-Pugh (CTP) score (p = 0.001) and comorbid shock (p = 0.005) were selected as independent clinical predictors of endoscopic hemostasis failure. High CTP score (p = 0.003) and the presence of gastric varices (p = 0.009) were related to early rebleeding after emergency endoscopic treatment. Furthermore, the 6-week mortality was significantly associated with MELD scores (p = 0.002), the presence of hepatic encephalopathy (p = 0.045) and postoperative rebleeding (p < 0.001). Finally, we developed practical nomograms to discern the risk of the emergency endoscopic hemostasis failure and 6-week mortality for EGVB patients. In conclusion, our study may help identify severe EGVB patients with higher hemostasis failure rate or 6-week mortality for earlier implementation of salvage treatments.
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Varizes Esofágicas e Gástricas , Hemorragia Gastrointestinal , Intubação Intratraqueal , Cirrose Hepática , Nomogramas , Humanos , Varizes Esofágicas e Gástricas/cirurgia , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Hemorragia Gastrointestinal/mortalidade , Hemorragia Gastrointestinal/cirurgia , Fatores de Risco , Cirrose Hepática/complicações , Intubação Intratraqueal/efeitos adversos , Estudos Retrospectivos , Idoso , Hemostase Endoscópica/métodos , Prognóstico , AdultoRESUMO
Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasing mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-ß. However, details of how HNF4α is suppressed are largely unknown to date. Herein, TGF-ß did not directly inhibit HNF4α but contributed to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α expressed both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lacked either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibited C/EBPα transcription. Long-term TGF-ß incubation resulted in C/EBPα depletion, which abrogated HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter was abolished by insulin. Two-thirds of patients without C/EBPα lacked membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, these data indicate that hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.
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Proteína de Ligação a CREB , Insulina , Humanos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína de Ligação a CREB/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Background: The advantages of spleen stiffness in prediction of high-risk varices (HRV) in cirrhosis patients have been confirmed. Recently, a new device utilizing a 100 Hz probe dedicated to spleen stiffness measurement (SSM) was developed. Objectives: To validate the clinical applicability of SSM@100 Hz in predicting HRV by comparing it with other non-invasive tests (NITs). Design: A prospective cohort study. Methods: A total of 171 cirrhosis patients who underwent esophagogastroduodenoscopy (EGD) examination were included in this study. SSM using a 100 Hz probe and liver stiffness measurement using a 50 Hz probe were performed. Additionally, 22 healthy controls underwent spleen stiffness evaluation using the 100 Hz probe. Results: The failure rates of spleen stiffness examination in patients with cirrhosis and in healthy controls were 2.9% and 4.5%, respectively. The means of SSM values were 56.4 ± 21.6 and 13.8 ± 6.7 kPa in cirrhosis and controls. SSM increased proportionally with the severity of esophageal varices. The area under receiver operating characteristic (ROC) for spleen stiffness in predicting HRV was 0.881 (95% confidence interval 0.829-0.934), with a cutoff value of 43.4 kPa. The accuracy, false negative rate and EGD spare rate were 86.5%, 2.5% and 24.3%, respectively. For HRV prediction, SSM was comparable to expanded Baveno VI and VII and superior to other NITs. As to viral versus non-viral cirrhosis and compensated versus decompensated cirrhosis, the cut-off and performance of SSM were different. Conclusion: SSM@100 Hz demonstrates high accuracy in predicting HRV with a low missed HRV rate. Our findings suggest that SSM@100 Hz can be used independently due to its simplicity and effectiveness. However, further studies are needed to determine appropriate cutoff values based on the cause of cirrhosis and liver function. Trail Registration: ChiCTR2300070270.
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OBJECTIVES: Long-term treatment with nucleoside analog (NA) reduces the risks for decompensation and hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with compensated cirrhosis (CC). However, whether antiviral therapy has differential efficacy on the risks for decompensation and HCC is insufficiently elucidated. Therefore, we investigated the disease state transition, focusing on decompensation event-specific HCC risk in NA-treated CHB patients with CC. METHODS: We prospectively followed up on 1163 NA-treated CHB patients with CC every six months for up to seven years. The cumulative incidence and risk of HCC were analyzed by the Kaplan-Meier method and competing risk model. The multistate model was used to estimate the transition probabilities to HCC from different disease states. RESULTS: HCC predominated the first liver-related events, with a 5-year cumulative incidence of 9.0%, followed by decompensation (8.3%, including 7.9% nonbleeding decompensation and 2.4% variceal bleeding) and 0.2% death. The decompensation stage had a significantly higher 5-year cumulative HCC incidence than the CC stage (27.6% vs. 9.1%; HR = 2.42, 95% CI: 1.24, 4.71). Furthermore, nonbleeding decompensation events had a higher 5-year transition probability to HCC than bleeding (27.6% vs. 15.8%; HR = 2.69, 95% CI: 1.41, 4.17). Viral suppression modified the on-treatment transition risk to HCC (1-year: HR = 0.45, 95% CI: 0.28, 0.73; 3-year: HR = 0.23, 95% CI: 0.14, 0.38). An online calculator was developed to facilitate HCC risk stratification. CONCLUSIONS: In NA-treated CHB patients with compensated cirrhosis, the risk was higher for HCC than for decompensation; more importantly, different decompensation events conferred distinct HCC risks.
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Carcinoma Hepatocelular , Varizes Esofágicas e Gástricas , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Vírus da Hepatite B , Varizes Esofágicas e Gástricas/complicações , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Antivirais/uso terapêutico , Hemorragia Gastrointestinal/complicações , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologiaRESUMO
AIM: To assess the correlation and agreement between hepatic venous pressure gradient (HVPG) and portal pressure gradient (PPG) in patients with autoimmune liver diseases (ALD) and portal hypertension, and to investigate the extent to which hepatic vein collateralization affects the accuracy of this assessment. METHODS: Ninety-eight patients with ALD between 2017 and 2021 who underwent transjugular intrahepatic portosystemic shunt with conventional and innovative 15 mL pressurized contrast were selected to measure wedged hepatic venous pressure (WHVP) and portal venous pressure and to calculate the HVPG and PPG. Pearson's correlation was used for correlation analysis between the two groups. Bland-Altman plots were plotted to estimate the agreement between paired pressures. RESULTS: The r values of PPG and HVPG in the early, middle, late, and portal venous visualization were 0.404, 0.789, 0.807, and 0.830, respectively, and the R2 values were 0.163, 0.622, 0.651, and 0.690, respectively. The p value for the r and R2 values in the early group was 0.015, and the p values in the remaining groups were less than 0.001. Bland-Altman plots showed that patients in the portal venous visualization group had the narrowest 95% limits of agreement. The mean value of the difference was close to the zero-scale line. CONCLUSIONS: In patients with ALD, the correlation between the HVPG and PPG was good, and the later the collateral development, the better the correlation. Hepatic vein collateral was an essential factor in underestimating WHVP and HVPG, and the earlier the collateral appeared, the more obvious the underestimation.
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BACKGROUND: Spontaneous fungal peritonitis (SFP) and fungiascites is less well-recognized and described in patients with liver cirrhosis. The aims of this study were to determine the clinical characteristics, prognosis, and risk factors of cirrhotic patients with SFP/fungiascites and to improve early differential diagnosis with spontaneous bacterial peritonitis (SBP). METHODS: This was a retrospective case-control study of 54 cases of spontaneous peritonitis in cirrhotic patients (52 SFP and 2 fungiascites) with fungus-positive ascitic culture. Fifty-four SBP cirrhotic patients with bacteria-positive ascitic culture were randomly enrolled as a control group. A nomogram was developed for the early differential diagnosis of SFP and fungiascites. RESULTS: Hospital-acquired infection was the main cause of SFP/fungiascites. Of the 54 SFP/fungiascites patients, 31 (57.41%) patients carried on with the antifungal treatment, which seemed to improve short-term (30-days) mortality but not long-term mortality. Septic shock and HCC were independent predictors of high 30-day mortality in SFP/fungiascites patients. We constructed a predictive nomogram model that included AKI/HRS, fever, (1,3)-ß-D-glucan, and hospital-acquired infection markers for early differential diagnosis of SFP/fungiascites in cirrhotic patients with ascites from SBP, and the diagnostic performance was favorable, with an AUC of 0.930 (95% CI: 0.874-0.985). CONCLUSIONS: SFP/fungiascites was associated with high mortality. The nomogram established in this article is a useful tool for identifying SFP/fungiascites in SBP patients early. For patients with strongly suspected or confirmed SFP/fungiascites, timely antifungal therapy should be administered.
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BACKGROUND: The hemodynamics of patients with cirrhosis and portal hypertension are complex and variable. We aimed to investigate differences in venous pressures determined by innovative angiography and conventional angiography using balloon occlusion of the hepatic veins in patients with alcoholic cirrhosis and portal hypertension. METHODS: A total of 134 patients with alcoholic cirrhosis who fulfilled the inclusion criteria from June 2017 to June 2020 were included. During transjugular intrahepatic portosystemic shunt, conventional and innovative angiography were performed, and venous pressures were measured. A paired t-test and Pearson's correlation coefficient were used for analysis. RESULTS: Conventional and innovative hepatic angiography detected lateral branches of the hepatic vein in 26 (19.4%) and 65 (48.5%) cases, respectively (P < 0.001). Innovative angiography detected a total of 65 patients with lateral shunts, of whom 37 (56.9%) had initial shunts. The average wedged hepatic venous pressure and portal venous pressure of the initial lateral branches were 21.27 ± 6.66 and 35.84 ± 7.86 mmHg, respectively, with correlation and determination coefficients of 0.342 (P < 0.05) and 0.117, respectively. The mean hepatic venous pressure gradient and portal pressure gradient were 9.59 ± 7.64 and 26.86 ± 6.78 mmHg, respectively, with correlation and determination coefficients of 0.292 (P = 0.079) and 0.085, respectively. CONCLUSIONS: Innovative angiography reveals collateral branches of the hepatic veins more effectively than conventional angiography. Hepatic vein collateral branches are the primary factors leading to underestimation of wedged hepatic venous pressures and hepatic venous pressure gradients, with the initial hepatic vein collateral branches resulting in the most severe underestimations.
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Veias Hepáticas , Hipertensão Portal , Humanos , Veias Hepáticas/diagnóstico por imagem , Cirrose Hepática Alcoólica , Hipertensão Portal/diagnóstico por imagem , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Angiografia , Veia Porta/diagnóstico por imagemRESUMO
BACKGROUND/AIMS: Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). METHODS: Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. RESULTS: The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65-0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61-0.68; untreated models: 0.51-0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. CONCLUSION: The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.
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Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Antivirais/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Vírus da Hepatite BRESUMO
This study sought to investigate risk factors for 6-week mortality of patients with decompensated liver cirrhosis associated esophagogastric variceal bleeding (EGVB) and clinical characteristics of myocardial injury in cirrhotic patients with EGVB. This retrospective cohort study included 249 patients with decompensated liver cirrhosis associated EGVB in the Department of Emergency. Patients were divided into two groups including liver cirrhosis associated EGVB without myocardial injury and liver cirrhosis associated EGVB with myocardial injury. Myocardial injury, recurrent bleeding, total bilirubin (TBIL) level and dyslipidemia are independent risk factors for 6-week mortality in liver cirrhosis associated EGVB. Among all patients with liver cirrhosis associated EGVB, 90 (36.2%) had myocardial injury and 159 individuals (63.8%) not. The 6-week mortality in the group with myocardial injury was 21%, which was significantly higher than that of 7% in the group without myocardial injury. More patients in the myocardial injury group smoked, had moderate to severe esophageal varices, liver failure, and Child-Pugh C liver function compared to the non-myocardial injury group. Myocardial injury, recurrent bleeding, TBIL level and dyslipidemia are independent risk factors for death within 6 weeks in liver cirrhosis associated EGVB. The 6-week mortality is considerably higher in patients with myocardial injury in liver cirrhosis associated EGVB than those without myocardial injury.
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Varizes Esofágicas e Gástricas , Humanos , Varizes Esofágicas e Gástricas/complicações , Estudos Retrospectivos , Hemorragia Gastrointestinal , Cirrose Hepática , Fatores de RiscoRESUMO
The pathogenesis of portal hypertension remains unclear, and is believed to involve dysfunction of liver sinusoidal endothelial cells (LSEC), activation of hepatic stellate cells (HSC), dysregulation of endogenous hydrogen sulfide (H2S) synthesis, and hypoxia-induced angiogenic responses. H2S, a novel gas transmitter, plays an important role in various pathophysiological processes, especially in hepatic angiogenesis. Inhibition of endogenous H2S synthase by pharmaceutical agents or gene silencing may enhance the angiogenic response of endothelial cells. Hypoxia-inducible factor-1 (HIF-1) is the main transcription factor of hypoxia, which induces hepatic angiogenesis through up-regulation of vascular endothelial growth factor (VEGF) in HSC and LSEC. H2S has also been shown to be involved in the regulation of VEGF-mediated angiogenesis. Therefore, H2S and HIF-1 may be potential therapeutic targets for portal hypertension. The effects of H2S donors or prodrugs on the hemodynamics of portal hypertension and the mechanism of H2S-induced angiogenesis are promising areas for future research.
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OBJECTIVE: Multidrug resistance protein 2 (MRP2) is a bottleneck in bilirubin excretion. Its loss is sufficient to induce hyperbilirubinaemia, a prevailing characteristic of acute liver failure (ALF) that is closely associated with clinical outcome. This study scrutinises the transcriptional regulation of MRP2 under different pathophysiological conditions. DESIGN: Hepatic MRP2, farnesoid X receptor (FXR) and Forkhead box A2 (FOXA2) expression and clinicopathologic associations were examined by immunohistochemistry in 14 patients with cirrhosis and 22 patients with ALF. MRP2 regulatory mechanisms were investigated in primary hepatocytes, Fxr -/- mice and lipopolysaccharide (LPS)-treated mice. RESULTS: Physiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. Fxr-/- mice lack apical MRP2 expression and rapidly progress into hyperbilirubinaemia. In patients with ALF, hepatic FXR expression is undetectable, however, patients without infection maintain apical MRP2 expression and do not suffer from hyperbilirubinaemia. These patients express FOXA2 in hepatocytes. FOXA2 upregulates MRP2 transcription through binding to its promoter. Physiologically, nuclear FOXA2 translocation is inhibited by insulin. In ALF, high levels of glucagon and tumour necrosis factor α induce FOXA2 expression and nuclear translocation in hepatocytes. Impressively, ALF patients with sepsis express low levels of FOXA2, lose MRP2 expression and develop severe hyperbilirubinaemia. In this case, LPS inhibits FXR expression, induces FOXA2 nuclear exclusion and thus abrogates the compensatory MRP2 upregulation. In both Fxr -/- and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels. CONCLUSION: FOXA2 replaces FXR to maintain MRP2 expression in ALF without sepsis. Ectopic FOXA2 expression to maintain MRP2 represents a potential strategy to prevent hyperbilirubinaemia in septic ALF.
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Fator 3-beta Nuclear de Hepatócito , Falência Hepática Aguda , Proteína 2 Associada à Farmacorresistência Múltipla , Animais , Camundongos , Bilirrubina , Fator 3-beta Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Hiperbilirrubinemia/metabolismo , Hiperbilirrubinemia/patologia , Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla/metabolismo , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
To standardize the diagnosis, treatment, and management of esophagogastric variceal bleeding (EVB) in patients with cirrhotic portal hypertension, the Chinese Society of Hepatology, the Chinese Society of Gastroenterology, and the Chinese Society of Digestive Endoscopy of the Chinese Medical Association brought together relevant experts, reviewed the latest national and international progress in clinical research on EVB in cirrhotic portal hypertension, and followed evidence-based medicine to update the Guidelines on the Management of EVB in Cirrhotic Portal Hypertension. The guidelines provide recommendations for the diagnosis, treatment, and management of EVB in cirrhotic portal hypertension and with the aim to improve the level of clinical treatment of EVB in patients with cirrhotic portal hypertension.
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BACKGROUND: Although transjugular intrahepatic portosystemic shunt (TIPS) is recommended for secondary prophylaxis of variceal bleeding if standard therapy fails and for patients with high risk of recurrent bleeding, no guidelines for the treatment of symptomatic portal hypertension in HCC patients are available. This study aimed to compare the efficacy and safety of TIPS with endoscopic + ß-blocker for prevention of the rebleeding in such patients. METHODS: 106 consecutive advanced HCC patients receiving tyrosine kinase inhibitor (TKI) who had been treated with vasoactive drugs plus endoscopic therapy for variceal bleeding were randomly assigned to receive either TIPS (n = 52) or endoscopic + ß-blocker therapy (n = 54) for the prevention of rebleeding. The primary endpoint was variceal rebleeding after randomization. RESULTS: During a median follow-up of 16 months, rebleeding occurred in 14 patients in the endoscopic + ß-blocker group and 3 patients in the TIPS group (p < 0.001). Forty-nine patients died (38 in endoscopic + ß-blocker group and 11 in TIPS group, p < 0.001). The 6-, 12-, and 18-month overall survival rates were 95, 81, and 73% for TIPS group and 35, 21, and 15% for endoscopic + ß-blocker group, respectively (p < 0.001). Eight patients in endoscopic + ß-blocker group received TIPS as rescue therapy, but two died. TKIs was discontinued in 32 patients, including 24 in the endoscopic + ß-blocker group and 8 in the TIPS group (p < 0.001). No significant differences were observed between the two groups with respect to serious adverse events. CONCLUSIONS: In advanced HCC patients receiving TKIs and presented with variceal bleeding, the use of TIPS was associated with significant reduction in rebleeding, improved a higher adherence to TKIs therapy, and prolonged survival.
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Carcinoma Hepatocelular , Varizes Esofágicas e Gástricas , Neoplasias Hepáticas , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/terapia , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Projetos Piloto , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Terapia de Alvo Molecular , Cirrose Hepática/etiologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Resultado do Tratamento , RecidivaRESUMO
BACKGROUND: Patients with hepatocellular carcinoma complicated with main portal vein tumor thrombosis (mPVTT) and cirrhotic portal hypertension (CPH) have an extremely poor prognosis, and there is a lack of a clinically effective treatment paradigm. AIM: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with radioactive seed strand for the treatment of mPVTT patients with CPH. METHODS: The clinical data of 83 consecutive patients who underwent TIPS combined with 125I seed strand placement for mPVTT and CPH from January 2015 to December 2018 were retrospectively reviewed. Procedure-related data (success rate, relief of portal vein pressure and CPH symptoms, and adverse events), PVTT response, and patient survival were assessed through a 2-year follow-up. RESULTS: The success rate was 100.0% without perioperative death or procedure-related severe adverse events. The mean portal vein pressure was significantly decreased after the procedure (22.25 ± 7.33 mmHg vs 35.12 ± 7.94 mmHg, t = 20.61, P < 0.001). The symptoms of CPH were all effectively relieved within 1 mo. The objective response rate of PVTT was 67.5%. During a mean follow-up of 14.5 ± 9.4 mo (range 1-37 mo), the cumulative survival rates at 6, 12 and 24 mo were 83.1%, 49.7%, and 21.8%, respectively. The median survival time was 12.0 ± 1.3 mo (95% confidence interval: 9.5-14.5). In multivariate Cox regression analysis, body mass index, Child-Pugh grade, cTNM stage, and PVTT response were independent prognostic factors (P < 0.05). CONCLUSION: TIPS combined with radioactive seed strand might be effective and safe in treating mPVTT patients with CPH.