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BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.
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Células Estrelladas Hepáticas , Hepatocitos , Cirrosis Hepática , Proteína de la Región Y Determinante del Sexo , Animales , Femenino , Masculino , Ratones , Tetracloruro de Carbono/toxicidad , Tetracloruro de Carbono/efectos adversos , Colestasis/genética , Colestasis/metabolismo , Colestasis/fisiopatología , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Ratones Noqueados , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Caracteres Sexuales , Proteína de la Región Y Determinante del Sexo/genética , Proteína de la Región Y Determinante del Sexo/metabolismoRESUMEN
BACKGROUND & AIMS: Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients. METHODS: Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs. RESULTS: A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 109/L). CONCLUSIONS: Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis.
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Hepatitis B Crónica , Hepatitis B , Neoplasias Hepáticas , Humanos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Hígado/patología , Cirrosis Hepática/complicaciones , Hepatitis B/complicaciones , Neoplasias Hepáticas/patología , Antivirales/uso terapéutico , BiopsiaRESUMEN
BACKGROUND: Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved. METHODS: The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen-glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection. RESULTS: Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells. CONCLUSIONS: Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.
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Cadenas beta de Integrinas , Factores de Transcripción de Tipo Kruppel , Hígado , Macrófagos , Daño por Reperfusión , Sevoflurano , Animales , Ratones , Apoptosis , Antígenos CD18/metabolismo , Antígenos CD18/genética , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/efectos de los fármacos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Hígado/metabolismo , Hígado/patología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Sevoflurano/farmacología , Activación Transcripcional , Cadenas beta de Integrinas/efectos de los fármacos , Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismoRESUMEN
INTRODUCTION: Portal hypertension progression can be relieved after controlling the etiology of liver cirrhosis. Whether beta-blockers could additionally enhance the effects during treatment, particularly for small esophageal varices (EV), was unclear. This study aims to assess the efficacy of add-on carvedilol to delay EV progression during anti-hepatitis B virus (HBV) treatment in HBV-related cirrhosis. METHODS: This randomized controlled trial enrolled patients with virologically suppressed HBV-compensated cirrhosis and small/medium EV. The participants were randomly assigned to receive nucleos(t)ide analog (NUC) or carvedilol 12.5 mg plus NUC (1:1 allocation ratio). The primary end point was the progression rate of EV at 2 years of follow-up. RESULTS: A total of 238 patients (small EV, 77.3%) were randomized into 119 NUC and 119 carvedilol plus NUC (carvedilol [CARV] combination group). Among them, 205 patients (86.1%) completed paired endoscopies. EV progression rate was 15.5% (16/103) in the NUC group and 12.7% (13/102) in the CARV combination group (relative risk = 0.79, 95% confidence interval 0.36-1.75, P = 0.567). Subgroup analysis on medium EV showed the CARV combination group had a more favorable effect in promoting EV regression (43.5% vs 13.1%, P = 0.022) than NUC alone, but not in small cases ( P = 0.534). The incidence of liver-related events (decompensation, hepatocellular carcinoma, or death/liver transplantation) within 2 years was similar between the 2 groups (11.2% vs 10.4%, P = 0.881). DISCUSSION: The overall results did not show statistically significant differences between the added carvedilol strategy and NUC monotherapy in preventing EV progression in patients with virologically suppressed HBV-compensated cirrhosis. However, the carvedilol-added approach might offer improved outcomes specifically for patients with medium EV (NCT03736265).
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Virus de la Hepatitis B , Neoplasias Hepáticas , Humanos , Carvedilol/uso terapéutico , Antivirales/uso terapéutico , Cirrosis Hepática/tratamiento farmacológicoRESUMEN
Liver cirrhosis remains a major health concern globally, but its epidemiology and etiology evolve with time. However, the changing pattern in etiology and cause of liver-related mortality for patients with cirrhosis are not fully elucidated. Herein, our aim was to characterize the temporal trend of the etiological spectrum and evaluate the impact of etiology on liver-related death among patients with compensated cirrhosis (CC) in Beijing, China. Clinical profiles of patients with CC discharged between January 2008 and December 2015 were retrieved from the Beijing hospital discharge database. The mortalities of different etiologies of cirrhosis were calculated. The risks of readmission and liver-related death associated with etiologies were evaluated by the Cox regression model. A total of 23 978 cirrhotic patients were included. The predominant cause was hepatitis B virus (HBV) (58.93%), followed by alcohol (21.35%), autoimmune (14.85%), miscellaneous etiologies (3.55%), and hepatitis C virus (HCV) (1.32%). From 2008 to 2015, the proportion of HBV-related cirrhosis decreased to 28.11%. Meanwhile, the proportions of autoimmune- and miscellaneous-related cirrhosis increased to 28.54% and 13.11%. The risk of liver-related death ranked the highest in patients with miscellaneous cirrhosis, followed by HBV-related cirrhosis, alcohol-related cirrhosis, autoimmune-related cirrhosis, and HCV-related cirrhosis. The 5-year rates of liver-related death were 22.56%, 18.99%, 18.77%, 16.01%, and 10.76%, respectively. HBV-related cirrhosis caused the highest risk of hepatocellular carcinoma (HCC)-related death, whereas alcohol- and miscellaneous-related cirrhosis caused higher risks of decompensation (DC)-related death than HBV-related cirrhosis, with hazard ratios of 1.35 (95% confidence interval [CI]: 1.24-1.48) and 1.20 (95% CI: 1.03-1.40), respectively. HBV remained a common cause of liver cirrhosis but gradually decreased. Mortality disparities existed in etiologies, with higher risks of HCC-related death in HBV-related cirrhosis, and DC-related death in alcohol- and miscellaneous-related cirrhosis.
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Carcinoma Hepatocelular , Hepatitis B , Hepatitis C , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiología , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Beijing/epidemiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Hepatitis C/complicaciones , Hepatitis C/epidemiología , Cirrosis Hepática Alcohólica , Virus de la Hepatitis B , HepacivirusRESUMEN
BACKGROUND AIMS: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. APPROACH RESULTS: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High , with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4 + activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation. CONCLUSIONS: The microfibrillar-associated protein 4 + -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.
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Matriz Extracelular , Cirrosis Hepática , Ratones , Animales , Humanos , Cirrosis Hepática/patología , Matriz Extracelular/metabolismo , Hígado/patología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismoRESUMEN
Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.
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Antivirales , ADN Viral , Virus de la Hepatitis B , Hepatitis B Crónica , Hígado , Integración Viral , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Antivirales/uso terapéutico , Masculino , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , Adulto , Femenino , Hígado/virología , Persona de Mediana Edad , ADN Viral/sangre , ADN Viral/genética , Guanina/análogos & derivados , Guanina/uso terapéutico , Interferón-alfa/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Estudios LongitudinalesRESUMEN
BACKGROUND: This study aimed to assess the global, regional, and national burden of liver cirrhosis and other chronic liver diseases between 1990 and 2019, considering five etiologies (hepatitis B, hepatitis C, alcohol use, NAFLD and other causes), age, gender, and sociodemographic index (SDI). METHODS: Data on liver cirrhosis and other chronic liver diseases mortality, incidence, and disability-adjusted life years (DALYs) were collected from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2019. RESULTS: In 2019, liver cirrhosis and other chronic liver diseases accounted for 1,472,011 (95% UI 1,374,608-1,578,731) deaths worldwide, compared to 1,012,975 (948,941-1,073,877) deaths in 1990. Despite an increase in absolute deaths, the age-standardized death rate declined from 24.43 (22.93-25.73) per 100,000 population in 1990 to 18.00 (19.31-16.80) per 100,000 population in 2019. Eastern sub-Saharan Africa exhibited the highest age-standardized death rate (44.15 [38.47-51.91] per 100,000 population), while Australasia had the lowest rate (5.48 [5.05-5.93] deaths per 100,000 population in 2019). The age-standardized incidence rate of liver cirrhosis and other chronic liver diseases attributed to hepatitis B virus has declined since 1990, but incidence rates for other etiologies have increased. Age-standardized death and DALYs rates progressively decreased with higher SDI across different GBD regions and countries. Mortality due to liver cirrhosis and other chronic liver diseases increased with age in 2019, and the death rate among males was estimated 1.51 times higher than that among females globally. CONCLUSION: Liver cirrhosis and other chronic liver diseases continues to pose a significant global public health challenge. Effective disease control, prevention, and treatment strategies should account for variations in risk factors, age, gender, and regional disparities.
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Hepatitis C , Enfermedad del Hígado Graso no Alcohólico , Muerte Perinatal , Masculino , Femenino , Humanos , Años de Vida Ajustados por Calidad de Vida , Cirrosis Hepática/epidemiología , Factores de Riesgo , Hepatitis C/complicaciones , Carga Global de Enfermedades , Salud Global , IncidenciaRESUMEN
Hepatic lobular architecture distortion is a deleterious turning point and a crucial histological feature of advanced liver fibrosis in chronic liver diseases. Regression of fibrosis has been documented in chronic hepatitis B (CHB) patients. However, whether lobular architecture could be restored following fibrosis regression after antiviral therapy is still unclear. Glutamine synthetase (GS) is generally expressed by perivenular hepatocytes around hepatic veins (HV). In this study, we defined abnormal lobular architecture (GSPT ) as GS expressing in the vicinity of portal tracts (PT), which denotes parenchymal extinction and lobular collapse. We defined normal lobular architecture (GSHV ) as GS positivity area not approximating PTs. Therefore, we propose a new GS-index, defined as the percentage of GSHV /(GSHV + GSPT ), to evaluate the extent of architectural disruption and restoration. We evaluated 43 CHB patients with advanced fibrosis (Ishak stage ≥4). Posttreatment liver biopsy was performed after 78 weeks of anti-HBV therapy. The median GS-index improved from 7% (interquartile range [IQR]: 0%-23%) at baseline to 36% (IQR: 20%-57%) at Week 78 (p < 0.001). Totals of 22 patients (51%) had significant GS-index improvement from 0% (IQR: 0%-13%) to 55% (IQR: 44%-81%), while the other half had almost no change between 17% (IQR: 0%-33%) to 20% (IQR: 12%-31%). When GS-index78w ≥ 50% was used to define hepatic lobular restoration, 37% of patients (16/43) achieved lobular restoration, with much improvement in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (median value of ∆/Baseline in ALT: restored vs. nonrestored was 79.1% vs. 48.8%, p = 0.018; median value of ∆/Baseline in AST: restored vs. nonrestored was 69.1% vs. 32.5%, p = 0.005). More importantly, lobular restoration correlated with fibrosis regression (median value of ∆/Baseline in Ishak stage: restored vs. nonrestored was 25.0% vs. 0%, p = 0.008). Therefore, in the era of antiviral therapy for CHB, restoration of hepatic lobular architecture is achievable in patients with advanced fibrosis. GS-index provides additional insight into fibrosis regression that goes beyond collagen degradation.
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Glutamato-Amoníaco Ligasa , Hepatitis B Crónica , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hígado/patología , Fibrosis , Cirrosis Hepática/patología , Alanina Transaminasa , Biopsia , Antivirales/uso terapéuticoRESUMEN
Despite the increasing prevalence of steatosis in patients with chronic hepatitis B (CHB), whether the changes in steatosis impact fibrosis regression during antiviral therapy remain unclear. We aimed to identify the association between histological changes of steatosis and fibrosis in patients undergone antiviral treatment. Patients with paired liver biopsies before and after 78 weeks of antiviral therapy were enrolled in this study. Liver fibrosis was assessed by the Ishak score combined with Beijing Classification predominantly progressive, indeterminate, and predominately regressive score. Steatosis was evaluated by the nonalcoholic fatty liver disease activity score. Collagen in each site was quantitated by second harmonic generation/two photon excitation fluorescence technology. Serum proteomic changes after treatment were characterized by mass-based spectrometry. A total of 239 CHB patients were included and divided into four groups according to the changes in steatosis: 162 (67.8%) had no steatosis throughout, 24 (10.0%) developed new-onset steatosis, 21 (8.8%) had initial steatosis which disappeared, and 32 (13.4%) had persistent steatosis. The persistent steatosis group showed the lowest rate of fibrosis regression (14/32, 43.8%). Persistent steatosis correlated with decreased fibrosis regression significantly after adjusting for age, sex, fibrosis stage, and metabolic factors at baseline, as well as the viral response (adjusted odds ratio = 0.380, 95% confidence interval 0.145-0.996, p = 0.049). This decreased fibrosis regression was associated with accumulated collagen in the perisinusoidal area. Patients with persistent steatosis showed unique changes in glycolipid metabolism according to the serum proteomic atlas. Persistent steatosis correlated with decreased fibrosis regression during antiviral therapy in patients with CHB.
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Hígado Graso , Hepatitis B Crónica , Humanos , Hígado/patología , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Antivirales/uso terapéutico , Proteómica , Hígado Graso/patología , Cirrosis Hepática/patología , Fibrosis , Colágeno/uso terapéuticoRESUMEN
OBJECTIVES: This study aimed to compare the YHLO chemiluminescence immunoassay (CLIA) with the Crithidia luciliae immunofluorescence test (CLIFT) to detect anti-dsDNA antibodies and its correlation with disease activity in systemic lupus erythematosus (SLE). METHOD: In total, 208 patients diagnosed with SLE, 110 other autoimmune patients, 70 infectious disorders patients, and 105 healthy people were enrolled in this study. Serum samples were tested using CLIA in a YHLO chemiluminescence system and CLIFT. RESULTS: The overall agreement between YHLO CLIA and CLIFT was 76.9% (160/208), with a moderate correlation (kappa = 0.530, p < 0.001). The sensitivity of YHLO CLIA and CLIFT were 58.2% and 55.3%, respectively. The specificity of YHLO CLIA and CLIFT were 95.1% and 99.3%, respectively. The sensitivity of YHLO CLIA was increased to 66.8% with a specificity of 93.6% when the cut-off value was set at 24 IU/mL. Spearman's correlation coefficient between the quantitative results of YHLO CLIA and the titers of CLIFT was 0.59 (p < .01). A significant correlation was found between the anti-dsDNA results detected by YHLO CLIA and the SLE Disease Activity Index 2000 (SLEDAI-2K). Spearman's correlation coefficient between YHLO CLIA and SLEDAI-2K (r = 0.66, p < .01) was higher than that of CLIFT (r = 0.60, p < .01). CONCLUSIONS: Good correlation and agreement were found between YHLO CLIA and CLIFT. In addition, there was a significant correlation between YHLO CLIA and the SLE Disease Activity Index, which was superior to that of CLIFT. The YHLO chemiluminescence system is recommended for the assessment of disease activity.
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Crithidia , Lupus Eritematoso Sistémico , Humanos , Sensibilidad y Especificidad , Luminiscencia , Anticuerpos Antinucleares , Técnica del Anticuerpo Fluorescente , Inmunoensayo , Ensayo de Inmunoadsorción Enzimática/métodosRESUMEN
BACKGROUND AND AIMS: Disease progression could be altered or even reversed in decompensated patients with HBV-related cirrhosis once they initiate antiviral therapy. However, little is known about the stable re-compensation in these patients. METHODS: In this retrospective study, HBV-related liver cirrhosis patients were consecutively enrolled at the first decompensated event of ascites or variceal hemorrhage (VH), and divided into immediate-treatment, on-treatment and delayed/no treatment groups. Patients were followed up to at least presence of second decompensation event or to June 2021. Re-compensation was defined as patients who did not occur second (further) decompensation during follow-up. RESULTS: A total of 130 HBV-related decompensated cirrhotic patients were included with a median follow-up of 61.0 (41.6, 72.0) months. The cumulative incidence of re-compensation at year 6 was 39.0, 9.8 and 6.6 in immediate-treatment, on-treatment and delayed/no treatment group (p = 0.001). Among 87 patients in immediate-treatment group, thirty-seven (37/87, 42.5%) were recognized as stable re-compensation. Seventy percent (35/50) of second decompensated events occurred in the first 2 years. In patients free of 2-year decompensated complications, about 71.2% (37/52) maintained stable re-compensation. The cumulative incidence of death (and/or transplantation) and HCC in patients free of 2-year decompensated complications or not was 2.9 vs. 27.3% (HR 9.4, 95% CI 2.2-40.0, p = 0.002) and 12.6 vs. 37.7% (HR 4.5, 95% CI 1.5-13.3, p = 0.006), respectively. CONCLUSIONS: In decompensated patients with HBV-related cirrhosis, about 40% in immediate-treatment group maintained stable re-compensation during 6 years of antiviral therapy. Two-year free of complications could predict stable re-compensation.
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Carcinoma Hepatocelular , Várices Esofágicas y Gástricas , Neoplasias Hepáticas , Humanos , Virus de la Hepatitis B , Várices Esofágicas y Gástricas/etiología , Estudios Retrospectivos , Hemorragia Gastrointestinal/etiología , Cirrosis Hepática/complicaciones , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: This study aimed to explore the risk factors for BK virus (BKV) infection in renal transplant recipients (RTRs) routinely treated with tacrolimus. METHODS: Forty-two cases with BKV infections and 51 patients without BKV infections were enrolled in the study. Eighty-seven healthy individuals and 77 patients undergoing dialysis were randomly included as controls. A logistic regression model was used to analyze potential variables in order to evaluate factors related to BKV infection in the renal transplant recipients. RESULTS: The number of individuals with acute rejection in BKV positive RTRs is significantly higher than that in BKV negative RTRs. Hemoglobin levels in BKV positive RTRs were significantly lower than those in BKV negative RTRs (109.61 ± 20.11 vs. 130.16 ± 26.297, p < 0.001). There was a positive correlation between tacrolimus levels and hemoglobin concentration in RTRs (r = 0.329, p = 0.023). The results of a multivariate regression analysis indicated that a history of acute rejection (OR = 4.157, p = 0.031) and low hemoglobin (OR = 0.963, p < 0.001) were risk factors for BKV infection. CONCLUSIONS: Acute rejection and low hemoglobin were risk factors for BKV infection after renal transplantation.
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Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Tacrolimus/uso terapéutico , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/etiología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/complicaciones , HemoglobinasRESUMEN
Alcohol use is a major risk factor for the burden of mortality and morbidity. Alcoholic cirrhosis (AC) and alcoholic liver cancer (ALC) are most important and severe liver disease outcomes caused by alcohol use. The objectives of the current study were to investigate the global prevalence and burden of disease in disability-adjusted life years (DALYs) for AC and ALC, based on data from the Global Burden of Disease (GBD). Incidence, prevalence, death, and DALYs for GBDs in different locations, years, sex, and age groups were estimated using DisMod-MR 2.1 and a generic Cause of Death Ensemble Modeling approach. The correlations between the age-standardized incidence rate or age-standardized death rate and gender, sociodemographic index (SDI), and alcohol usage were conducted by Generalized Linear Models. Globally, the changes of age-standardized rates of indicators were not much significant over the 30-year period. However, the changes varied widely across regions. Central Asia and East Europe contributed the highest age-standardized incidence, prevalence, death, and DALYs and increased sharply by past 30 years. Generalized Linear Models (GLMs) showed male gender as a risk factor of AC, with the relative risk of incidence of 1.521 and relative risk of death of 1.503. Globally, there were improvements in overall health with regard to GBDs over the 30 years. However, the prevention of AC and ALC should be promoted in middle and middle-high SDI regions, especially Central Asia and East Europe, whereas more medical resources should be provided to improve treatment levels in low SDI region.
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Carga Global de Enfermedades , Hepatopatías Alcohólicas , Humanos , Masculino , Adulto , Años de Vida Ajustados por Calidad de Vida , Factores de Riesgo , Hepatopatías Alcohólicas/epidemiología , Prevalencia , Incidencia , Cirrosis Hepática Alcohólica , Salud GlobalRESUMEN
OBJECTIVES: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury. BACKGROUND: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined. METHODS: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation. RESULTS: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin, and promotes phosphorylation and degradation of ß-catenin, leading to suppression of the downstream FOXOs, and activation of NF-κBand TLR4 signaling. Furthermore, activation of ß-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage. CONCLUSIONS: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/ß-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries.
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Hepatopatías , Daño por Reperfusión , Proteína de la Región Y Determinante del Sexo/metabolismo , Animales , Apoptosis , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Isquemia , Hígado/patología , Hepatopatías/metabolismo , Masculino , Ratones , Caracteres Sexuales , beta CateninaRESUMEN
INTRODUCTION: To assess comparative performance of 14 hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients using on-treatment values at different timepoints. METHODS: Based on a nationwide prospective cohort of 986 treatment-naive CHB patients undergoing entecavir therapy with every 26-week follow-up, 14 HCC risk scores were calculated using on-treatment values at week 26, 52, 78, and 104, respectively. Model performance predicting 3-year HCC was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and calibration index. Model cutoffs were validated through common diagnostic accuracy measures. RESULTS: During median 4.7-year follow-up, 56 (7.5%) developed HCC. Discrimination using on-treatment values within first 2 years was generally acceptable for most models (AUCs ranging from 0.68 to 0.81), except for REACH-B, NGM-HCC, and PAGE-B, although AUCs slightly decreased from week 26 to 104. Of these, REAL-B, CAMD, GAG-HCC, AASL-HCC, LSM-HCC, mPAGE-B, and mREACH-BII showed highest discrimination with AUCs ranging from 0.76 to 0.81, 0.72 to 0.76, 0.70 to 0.76, and 0.71 to 0.74 when reassessment at week 26, 52, 78, and 104, respectively. With reassessment within first 2 years, both REAL-B and CAMD calibrated well (Brier score ranging from 0.037 to 0.052). Of 9 models reporting cutoffs, REAL-B, AASL-HCC, and mPAGE-B using on-treatment values could identify 30%-40% of patients as low risk with minimal HCC incidence in the low-risk group (0.40% [REAL-B]-1.56% [mPAGE-B]). DISCUSSION: In this undergoing antiviral treatment CHB cohort, most HCC prediction models performed well even using on-treatment values during first 2 years, particularly REAL-B, AASL-HCC, CAMD, and mPAGE-B model.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de RiesgoRESUMEN
Nonalcoholic steatohepatitis (NASH) is increasingly recognized as a serious disease that can lead to cirrhosis, hepatocellular carcinoma (HCC), and death. However, there is no effective drug to thwart the progression of the disease. Development of new drugs for NASH is an urgent clinical need. Liver biopsy plays a key role in the development of new NASH drugs. Histological findings based on liver biopsy are currently used as the main inclusion criteria and the primary therapeutic endpoint in NASH clinical trials. However, there are inherent challenges in the use of liver biopsy in clinical trials, such as evaluation reliability, sampling error, and invasive nature of the procedure. In this article, we review the advantages and value of liver histopathology based on liver biopsy in clinical trials of new NASH drugs. We also discuss the challenges and limitations of liver biopsy and identify future drug development directions.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Biopsia , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Desarrollo de Medicamentos , Humanos , Hígado/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND & AIMS: The aim of our study was to characterize the performance of hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients through meta-analysis followed by external validation. METHODS: We performed a systematic review and meta-analysis of current literature, followed by external validation in independent multi-center cohort with 986 patients with CHB undergoing entecavir treatment (median follow-up: 4.7 years). Model performance to predict HCC within 3, 5, 7, and 10 years was assessed using area under receiver operating characteristic curve (AUROC) and calibration index. Subgroup analysis were conducted by treatment status, cirrhotic, race and baseline alanine aminotransferase. RESULTS: We identified 14 models with 123,885 patients (5,452 HCC cases), with REACH-B, CU-HCC, GAG-HCC, PAGE-B and mPAGE-B models being broadly externally validated. Discrimination was generally acceptable for all models, with pooled AUC ranging from 0.70 (95% CI, 0.63-0.76 for REACH-B) to 0.83 (95% CI, 0.78-0.87 for REAL-B) for 3-year, 0.68 (95% CI, 0.64-0.73 for REACH-B) to 0.81 (95% CI, 0.77-0.85 for REAL-B) for 5-year and 0.70 (95% CI, 0.58-0.80 for PAGE-B) to 0.81 (95% CI, 0.78-0.84 for REAL-B and 0.77-0.86 for AASL-HCC) for 10-year prediction. However, calibration performance was poorly reported in most studies. In external validation cohort, REAL-B showed highest discrimination with 0.76 (95% CI, 0.69-0.83) and 0.75 (95% CI, 0.70-0.81) for 3 and 5-year prediction. The REAL-B model was also well calibrated in the external validation cohort (3-year Brier score 0.066). Results were consistent in subgroup analyses. CONCLUSIONS: In a systematic review of available HCC models, the REAL-B model exhibited best discrimination and calibration.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamiento farmacológico , Estudios de Cohortes , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Non-invasive assessment criteria to rule out high-risk varices (HRV) in compensated hepatitis B virus (HBV) cirrhosis on antiviral therapy remains unclear. METHODS: HBV-related compensated cirrhotic patients who underwent screening endoscopy during antiviral therapy were enrolled and randomly divided into the derivation and validation sets. HRV were defined as medium to large varices or small varices with red signs. Univariate and multivariate logistic analysis were used to determine the parameters associated with HRV. RESULTS: A total of 436 HBV-related compensated cirrhotic patients screened for varices were enrolled, the median duration of antiviral therapy was 4 years (IQR: 2.5-5.5 years). In the derivation set (N = 290, 17.2% with HRV), only platelet (PLT) count (OR = 0.972, 95% CI 0.961-0.984, P < .05) was independently associated with HRV, whereas liver stiffness measurement was not associated with the presence of HRV. With a PLT count cut-off value of 105 × 109 /L, unnecessary endoscopies could be spared in 56.9% patients, with a 3.6%. risk of missing HRV. In the validation cohort (N = 146, 16.4% with HRV), the proportion of patients that could safely spare endoscopies (61.0%) identified by this PLT count cut-off value was higher than that obtained by using Baveno VI criteria (34.9%), with an acceptable risk of missing HRV (3.4%). CONCLUSION: Compared with the 'Baveno VI criteria or beyond' criteria, PLT count higher than 105 × 109 /L could safely spare more screening endoscopies without increasing the risk of missing HRV in patients with HBV-related compensated cirrhosis on antiviral therapy.
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Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Várices , Antivirales/uso terapéutico , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/etiología , Virus de la Hepatitis B , Humanos , Cirrosis Hepática/complicacionesRESUMEN
BACKGROUND & AIMS: C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. METHODS: PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp-/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro. RESULTS: In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl4-induced hepatic injury, the infiltration of macrophages and CCR2+ monocytes into the liver was significantly decreased in Psmp-/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp-/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. CONCLUSION: PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. LAY SUMMARY: Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo. These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.