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OBJECTIVES: Hepatic inflammation, the driver of fibrosis progression in liver disease, can impact the accuracy of liver stiffness measurement (LSM). We wondered whether the decline in LSM value during the early antiviral phase was mainly attributed to the control of hepatic inflammation or the regression of fibrosis in patients with fibrotic/cirrhotic chronic hepatitis B (CHB). PATIENTS AND METHODS: The study cohort was composed of 82 patients with CHB who underwent antiviral and antifibrotic therapy at the Fifth Medical Center of PLA General Hospital. All patients had liver biopsies at both baseline and 72 weeks posttherapy. Liver pathology and clinical data, including the LSM value, were collected. RESULTS: After 72 weeks of treatment, both the histologic activity index score and fibrosis score, as well as the LSM value, were significantly decreased (P < 0.001), compared with their baseline values. The pretreatment correlation of LSM value with either histologic activity index score (r = 0.526 vs r = 0.286) or fibrosis score (r = 0.677 vs r = 0.587) was attenuated at 72 weeks. Notably, logistic regression analysis revealed that the improvement in inflammation (odds ratio = 1.018, 95% CI: 1.002-1.031, P = 0.023) but not fibrosis (odds ratio = 0.994, 95% CI: 0.980-1.009, P = 0.414), had an impact on the change in LSM values between baseline and at 72-week treatment. CONCLUSIONS: The findings of this study suggest that in patients with fibrotic CHB receiving antiviral medication, the early phase reduction in LSM value was related to improved hepatic inflammation rather than fibrosis regression.
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This study was designed to explore if antiviral treatment influences the performance of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high-risk chronic HBV-infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non-antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non-antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut-off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high-risk population of CHB and LC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , Virus de la Hepatitis B , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Estudios Retrospectivos , alfa-FetoproteínasRESUMEN
BACKGROUND AND AIM: Golgi protein 73 (GP73) is a transmembrane protein that can promote the proliferation of cancer cells. However, the roles of GP73 in the proliferation of non-malignant hepatocytes have rarely been investigated. METHODS: The wild-type (GP73+/+ ) and GP73 gene knockout mice (GP73-/- ) were subject to 70% partial hepatectomy (PHx) to explore the involvement of GP73 in liver regeneration. RESULTS: After PHx, a significant increase of GP73 expression was observed in GP73+/+ mouse liver. Noticeably, promoted recovery of liver mass was observed in GP73-/- mouse at Day 1 after PHx, as showed by the liver/body weight ratio. RNA sequencing revealed that genes relevant to cell cycle and inflammation response in the residual liver tissues were severely suppressed with the deletion of GP73, particularly the inactivation of NF-κB signal pathway in early phase of liver regeneration. In line with this, we do see the downregulation of cell cycle-related protein including cyclin D1, p-cyclin D1, ß-catenin, as well as interleukin 6, tumor necrosis factor-α, CCl2, and CXCl10. In contrast, activation of mTOR signaling pathway was documented, accompanied with the histological hypertrophy of hepatocytes in GP73-/- mouse. CONCLUSIONS: Golgi protein 73 deletion leads to delayed response of liver regeneration and inflammation in the early stages of liver regeneration after PHx.
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Proliferación Celular/genética , Eliminación de Gen , Hepatocitos/fisiología , Regeneración Hepática/genética , Regeneración Hepática/fisiología , Proteínas de la Membrana/fisiología , Fosfoproteínas/fisiología , Animales , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Diacylglycerol kinases (DGK) are a family of enzymes catalyzing the transformation of diacylglycerol into phosphatidic acid, which have been recognized as key regulators in cell signaling pathways. The role of DGKγ in human malignancies has seldom been studied. In this study, we investigated the role of DGKγ in hepatocellular carcinoma (HCC). We found that DGKγ was down-regulated in HCC tumor tissues and cell lines as compared to that in non-tumor tissues. The prognostic value of DGKγ expression was evaluated by Cox regression and Kaplan-Meier analyses. Lower DGKγ expression in tumor tissues was an independent prognostic factor for poor post-surgical overall survival. By using HDACs inhibitors treatment and ChIP-PCR, we discovered that histone H3 and H4 deacetylation mainly contributed to the downregulation of DGKγ expression. Functional studies revealed that ectopic expression of DGKγ inhibited cell proliferation and cell migration in HCC cells. Mechanism studies showed that DGKγ overexpression led to down regulation of GLUT1 protein level and AMPK activity, which result in glucose uptake suppression as well as lactate and ATP production declination. The decrease of GLUT1 level could be partially rescued by treatments with either DGK inhibitor and lysosome inhibitor, indicating DGKγ may down-regulate GLUT1 through its kinase activity and lysosome degradation process. Together, this study demonstrated that DGKγ plays a tumor suppressor role in HCC by negatively regulating GLUT1. DGKγ could be a novel prognostic indicator and therapeutic target for HCC.
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Carcinoma Hepatocelular/enzimología , Diacilglicerol Quinasa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Neoplasias Hepáticas/enzimología , Proteínas Supresoras de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Movimiento Celular , Diacilglicerol Quinasa/genética , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Glucosa/metabolismo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Pronóstico , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/genéticaRESUMEN
OBJECTIVE: To investigate the changes in red blood cell count in patients with different liver diseases and the correlation between red blood cell count and degree of liver damage. METHODS: The clinical data of 1427 patients with primary liver cancer, 172 patients with liver cirrhosis, and 185 patients with hepatitis were collected, and the Child-Pugh class was determined for all patients. The differences in red blood cell count between patients with different liver diseases were retrospectively analyzed, and the correlation between red blood cell count and liver function status was investigated. The Mann-Whitney U test, Kruskal-Wallis H test, rank sum test, Spearman rank sum correlation test, and chi-square test were performed for different types of data. RESULTS: Red blood cell count showed significant differences between patients with chronic hepatitis, liver cancer, and liver cirrhosis and was highest in patients with chronic hepatitis and lowest in patients with liver cirrhosis (P < 0.05). In the patients with liver cirrhosis, red blood cell count tended to decrease in patients with a higher Child-Pugh class (P < 0.05). CONCLUSION: For patients with liver cirrhosis, red blood cell count can reflect the degree of liver damage, which may contribute to an improved liver function prediction model for these patients.
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Recuento de Eritrocitos , Hepatitis/sangre , Cirrosis Hepática/sangre , Neoplasias Hepáticas/sangre , Humanos , Hígado/fisiopatología , Estudios RetrospectivosRESUMEN
The G870A polymorphism in the exon 4/intron 4 boundary of CCND1 gene is thought to influence the generation of two mRNAs (cyclin D1a and cyclin D1b). The "A" allele codes for a truncated variant, cyclin D1b, which may have higher transforming activity. Herein, the tumor relevance of G870A polymorphism, the association between cyclin D1 variant expression and G870A genotype, and the oncogenic potential of cyclin D1 variants in HBV-related hepatocellular carcinoma (HCC) were examined. We found that there is no significant difference of G870A distribution among the HCC, chronic HBV (CHB) infection, cirrhotic CHB, and healthy control groups. Stratification analysis revealed that in younger patients (ages ≤ 50), cirrhotic CHB patients with AA genotype had an increased risk of developing HCC with odds ratio of 1.943 (95 % CI 1.022-3.694, p = 0.0411) as compared with AG/GG genotypes. The two variants were both transcripted from "A" and "G" alleles, and neither cyclin D1a nor D1b production was influenced by G870A genotype in HCC. The expression of both cyclins D1a and D1b decreased in HCC tissues (p = 0.003, p = 0.005), while increased in adjacent nontumor tissues as compared with normal liver tissues (p = 0.045, p = 0.034). Overexpression of cyclin D1a or D1b could promote the cell proliferation and cell-cycle progression in Huh-7 and LO2 cell lines. Collectively, our data suggest that G870A polymorphism has only very limited predictive value for HBV-related HCC. Both cyclins D1a and D1b could promote cell proliferation, which might contribute to the potential oncogenic role of cyclin D1 variants during the precancerous cirrhotic stage of hepatocarcinogenesis.
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Carcinoma Hepatocelular/genética , Ciclina D1/genética , Neoplasias Hepáticas/genética , Adulto , Empalme Alternativo/genética , Pueblo Asiatico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Ciclina D1/biosíntesis , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Virus de la Hepatitis B/patogenicidad , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: There is lack of reliable serum biomarkers to reflect the severity of liver necroinflammation for those who suffer autoimmune liver diseases (AILDs). In this study, a previously established patient cohort was used to explore the potential of serum Golgi protein 73 (GP73) as a noninvasive marker of AILD-related liver necroinflammation. METHODS: Serum GP73 concentration was measured in a retrospective cohort of 168 AILD patients, which included 74 patients with autoimmune hepatitis (AIH) and 94 with primary biliary cholangitis (PBC) who had undergone liver biopsy. Spearman's correlation and multivariate analysis were used to evaluate the relationship between serum GP73 and liver necroinflammation. A receiver operating characteristic curve was constructed to evaluate the value of GP73 for the prediction of moderate or severe liver necroinflammation. The diagnostic value of serum GP73 was also compared with that of alkaline phosphatase (ALP) in patients with PBC. Histologically, immunohistochemical analysis was performed to assess hepatic GP73 expression. RESULTS: Both the serum level and hepatic tissue expression of GP73 protein were aberrantly elevated and correlated well with the severity of necroinflammation in both AIH (rho = 0.655, P < 0.001) and PBC (rho = 0.547, P < 0.001) patients. The results here suggested that serum GP73 could be an independent biomarker to reflect the severity of liver necroinflammation. The AUROCs for GP73 to predict moderate necroinflammation (≥G2) and severe necroinflammation (≥G3) in patients with AIH were 0.828 and 0.832, respectively. Moreover, the AUROCs of serum GP73 for the identification of moderate necroinflammation (≥G2) (AUROC = 0.820, P < 0.001) and severe necroinflammation (≥G3) (AUROC = 0.803, P < 0.001) were superior to those of ALP (≥G2: AUROC = 0.607, P = 0.028 and ≥G3: AUROC = 0.559, P = 0.357) in patients with PBC. Mechanically, interlukin-6 (IL-6), the proinflammatory and prohepatic regenerating cytokine, could transcriptionally upregulate GP73 gene expression. CONCLUSION: Serum GP73 is a potential noninvasive biomarker to evaluate the severity of liver necroinflammation in patients with AILDs.
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Hepatitis Autoinmune/metabolismo , Cirrosis Hepática Biliar/metabolismo , Proteínas de la Membrana/metabolismo , Adulto , Biomarcadores/metabolismo , Pruebas Diagnósticas de Rutina , Progresión de la Enfermedad , Femenino , Hepatitis Autoinmune/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
Background and Aims: As a hepatocellular carcinoma biomarker, serum Golgi protein 73 (GP73) is reportedly related to inflammation. Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation. In this study, we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF (ALD-ACLF). Methods: This retrospective cohort study involved 126 Chinese adults with ALD-ACLF. Baseline serum GP73 level was measured using enzyme-linked immunosorbent assay. Patients were followed-up for 90 d and outcomes were assessed. Data were analyzed using multivariate Cox regression and piecewise linear regression analyses. The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves. Results: The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF. Compared with the lowest tertile, the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model [at 28 days: hazard ratio (HR): 4.29 (0.99-18.54), p=0.0511; at 90 days: HR: 3.52 (1.15-10.79), p=0.0276]. Further analysis revealed a positive linear association. GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-sodium score in predicting short-time prognosis of patients with ALD-ACLF. Conclusions: The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF. GP73 improved the predictive value of classic prognostic scores.
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Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients (r = 0.540, p < 0.001), higher than that in non-cirrhotic CLD (r = 0.318, p < 0.001) and HCC (r = 0.353, p < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.
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Ácido Desoxicólico/metabolismo , Hepatopatías/metabolismo , Proteínas de la Membrana/biosíntesis , Subunidad p50 de NF-kappa B/biosíntesis , Regulación hacia Arriba , Adulto , Animales , Ácidos y Sales Biliares/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Enfermedad Crónica , Ácido Desoxicólico/farmacología , Femenino , Fibrosis , Perfilación de la Expresión Génica , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Hepatopatías/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Persona de Mediana Edad , Fosfoproteínas/biosíntesis , Estudios RetrospectivosRESUMEN
AIMS: Persistent hepatic necroinflammatory damage almost always results in fibrosis/cirrhosis or even hepatocellular carcinoma. Therefore, the presence of active necroinflammation in the liver suggests that nonalcoholic fatty liver disease (NAFLD) patients are in urgent need of treatment. Unfortunately, alanine transaminase (ALT), a routine indicator of liver inflammatory damage, showed a poor performance in nonalcoholic steatohepatitis (NASH) patients. Thus, it will be valuable to find an alternative indicator to identify patients with hepatic necroinflammatory damage. In this study, we evaluated the diagnostic value of serum Golgi protein 73 (GP73) for hepatic necroinflammatory damage in patients with NASH. METHODS: The clinical data of 201 patients with NASH diagnosed by liver biopsy according to the Brunt staging system were collected retrospectively. The in situ expression of GP73 protein was measured by immunohistochemistry. The receiver operating characteristic (ROC) curve was used to calculate the area under the ROC curve (AUROC) of serum GP73 for diagnosing hepatic necroinflammatory damage. RESULTS: The serum GP73 levels of NASH patients increased with the aggravation of liver necroinflammation. The median levels significantly increased from 49.98 ng/ml (31.49, 75.05) for G0-1 to 76.61 ng/ml (48.68, 110.03) for G2 and to 116.44 ng/ml (103.41, 162.17) for G3 patients (G0-1 vs. G2, P < 0.0001; G2 vs. G2, P < 0.0001; G2. CONCLUSIONS: GP73 is a valuable alternative serum marker reflecting the severity of hepatic necroinflammation in NASH patients.
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Biomarcadores/sangre , Inflamación/diagnóstico , Cirrosis Hepática/diagnóstico , Proteínas de la Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Curva ROC , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: In previous research, we have demonstrated that sodium tanshinone IIA sulfonate (STS) has anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity, but whether autophagy is involved in this process is still unknown. In this study, the autophagy effect of STS against PRRSV infection was investigated in vitro. METHODS: Quantitative real-time PCR (qRT-PCR) and western blot was used to evaluate the inhibition ability of STS on the mRNA expression levels on cell autophagy genes, that is Beclin1, ATG5 and ATG7. Simultaneously, the effect of STS on N protein/gene expression was assessed by indirect immuno-fluorescence assay (IFA), qRT-PCR and western blot. RESULTS: The results indicated that STS inhibits autophagy induced by PRRSV. In addition, STS effectively suppresses PRRSV's N protein replication and N gene expression in Marc-145 cells infected with PRRSV in a time-dependent manner. CONCLUSIONS: Our results suggest that STS exhibits anti-PRRSV activity in vitro by suppressing autophagy-related genes, which may provide a theoretical basis for further pharmacological agent development regarding PRRSV infection.
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Proteínas Relacionadas con la Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/metabolismo , Fenantrenos/farmacología , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Antivirales/farmacología , Autofagia , Proteína 5 Relacionada con la Autofagia/efectos de los fármacos , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteína 7 Relacionada con la Autofagia/efectos de los fármacos , Proteína 7 Relacionada con la Autofagia/metabolismo , Beclina-1/efectos de los fármacos , Beclina-1/metabolismo , Línea Celular , Técnicas In Vitro , Proteínas de la Nucleocápside/efectos de los fármacos , Proteínas de la Nucleocápside/metabolismo , Virus del Síndrome Respiratorio y Reproductivo Porcino/efectos de los fármacos , Virus del Síndrome Respiratorio y Reproductivo Porcino/metabolismoRESUMEN
AIMS: To date, curative resection remains to be the most optimal therapeutic choice of hepatocellular carcinoma (HCC), though the overall survival (OS) remains extremely unsatisfactory. To better manage the HCC patients, we evaluated the prognosis predicting values of apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) on the long-time survival of patients who underwent surgical treatment in this study. METHODS: A subgroup of 164 patients from our previously described follow-up cohort were enrolled in this study, of whom the pre-surgery ApoB and LDL-C measurements were available. They had been followed until January 2017, with a 19.5 months median survival time. The prognosis predicting values of serum ApoB, LDL-C, and other clinical variables were evaluated through Cox univariate and multivariate analyses, meanwhile, Kaplan-Meier analysis was conducted to obtain the OS curves. RESULTS: Pre-surgery ApoB was an independent prognosis predicting factor with HR as 1.396 (P=0.033), elevated ApoB was associated with worse postsurgery prognosis in HCC patients. Concordantly, Spearman's correlation analysis revealed that value of pre-surgery ApoB was to some extent correlated with tumor size (r=0.355, P<0.001). In line with this, further univariate and multivariate logistic regression analysis revealed that patients with higher ApoB value were more likely to have larger tumor size (≥5 cm), with the OR value as high as 2.221 (95% CI: 1.288-3.830, P=0.004). Additionally, level of ApoB was found to be highly correlated with the serum level of LDL-C (r=0.686, P<0.001). CONCLUSION: ApoB could be a valuable novel prognosis predicting marker for HCC patients who underwent curative liver resection. Moreover, elevated ApoB level could indicate worse outcome in HCC patients, which could be explained by the relationship between ApoB and residual liver function.
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BACKGROUND: Non-invasive method to identify chronic hepatitis B (CHB) patients with at least moderate inflammatory lesion but no increased ALT is an unmet need. We evaluated Golgi protein 73 (GP73) based hepatic inflammation model (HIM) as a serum surrogate for liver necroinflammatory activity, especially in those with ALT less than traditional upper concentration. METHODS: The diagnostic performances of HIM were evaluated in 2 independent cohorts of liver biopsy proved CHB patients by receiver operating characteristic (ROC) curve analysis. RESULTS: HIM, a suggested index combined GP73, gamma-glutamyltransferase and AST, could significantly improve the diagnostic accuracy for liver necroinflammation (Area under ROC, AUROC: 0.890). More importantly, HIM still exhibit excellent diagnostic value (AUROC: 0.873) to identify patients with at least moderate liver necroinflammatory activity but with ALT <40â¯U/l. Serum GP73 was the major source of improvement for diagnostic model's accuracy. CONCLUSION: HIM is probably a promising non-invasive index to identify CHB patients with moderate to severe liver necroinflammation, especially in those with ALT <40â¯U/l.
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Alanina Transaminasa/sangre , Hepatitis B Crónica/sangre , Hepatopatías/sangre , Proteínas de la Membrana/sangre , gamma-Glutamiltransferasa/sangre , Adulto , Estudios de Cohortes , Femenino , Hepatitis B Crónica/metabolismo , Humanos , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND AND AIM: Serum Golgi protein 73 (GP73) is a promising alternative biomarker of chronic liver diseases, but most data are from patients with HBV infection rather than HCV. MATERIALS AND METHODS: Two independent cohorts of chronic hepatitis C (CHC) patients from the 5th Medical Centre of the Chinese PLA General Hospital (n = 174) and Beijing Youan Hospital (n = 120) with different histories of HCV infection were enrolled. The correlations between serum GP73 and other biochemical indices, as well as its correlations with different stages of liver disease progression, were investigated. The receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic potential of serum GP73 for liver necroinflammation and fibrosis, and comparisons of the diagnostic efficiency with traditional indices of hepatic liver injuries were further investigated. RESULTS: Levels of serum GP73 were found significantly elevated in patients with moderate to severe inflammatory grade (G ≥ 2) and/or with advanced fibrotic stages (F ≥ 3) in both cohorts (P < 0.05, respectively), as compared to those with a normal or mild liver lesion. Further ROC analysis demonstrated that serum GP73 was comparable to serum ALT and AST in diagnosing the liver necroinflammation grade at G ≥ 2, but its diagnostic values for advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) were limited when compared to APRI and FIB-4, and FIB-4 exhibited the best performance. Notably, an obvious elevation of serum GP73 was observed after patients received PEG-IFN and ribavirin treatment. CONCLUSIONS: Serum GP73 is an important biomarker in evaluating and monitoring the disease progression including liver necroinflammation and fibrosis in patients with chronic HCV infection, but the value is limited for diagnosing advanced fibrosis and cirrhosis in comparison with APRI and FIB-4.
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Enfermedad Hepática en Estado Terminal/sangre , Hepatitis C Crónica/sangre , Cirrosis Hepática/sangre , Proteínas de la Membrana/sangre , Adulto , Biomarcadores/sangre , Progresión de la Enfermedad , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Femenino , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Inflamación , Interferón-alfa/uso terapéutico , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Polietilenglicoles , Curva ROC , Ribavirina/uso terapéutico , Resultado del TratamientoRESUMEN
Background and Aims: Non-invasive evaluation of liver necroinflammation in patients with chronic liver disease is an unmet need in clinical practice. The diagnostic accuracy of transient elastography-based liver stiffness measurement (LSM) for liver fibrosis could be affected by liver necroinflammation, the latter of which could intensify stiffness of the liver. Such results have prompted us to explore the diagnosis potential of LSM for liver inflammation. Methods: Three cross-sectional cohorts of liver biopsy-proven chronic liver disease patients were enrolled, including 1417 chronic hepatitis B (CHB) patients from 10 different medical centers, 106 non-alcoholic steatohepatitis patients, and 143 patients with autoimmune-related liver diseases. Another longitudinal cohort of 14 entecavir treatment patients was also included. The receiver operating characteristic (ROC) curve was employed to explore the diagnostic value of LSM. Results: In CHB patients, LSM value ascended with the increased severity of liver necroinflammation in patients with the same fibrosis stage. Such positive correlation between LSM and liver necroinflammation was also found in non-alcoholic steatohepatitis and autoimmune-related liver diseases populations. Furthermore, the ROC curve exhibited that LSM could identify moderate and severe inflammation in CHB patients (area under the ROC curve as 0.779 and 0.838) and in non-alcoholic steatohepatitis patients (area under the ROC curve as 0.826 and 0.871), respectively. Such moderate diagnostic value was also found in autoimmune-related liver diseases patients. In addition, in the longitudinal entecavir treated CHB cohort, a decline of LSM values was observed in parallel with the control of inflammatory activity in liver. Conclusions: Our study implicates a diagnostic potential of LSM to evaluate the severity of liver necroinflammation in chronic liver disease patients.
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Background and Aims: The poor outcomes of hepatocellular carcinoma (HCC) patients may be due to not only malignant tumors but also limited liver function. Therefore, as stated in major guidelines, only patients with relatively normal liver function (Child-Pugh A) would be referred for curative hepatectomy. Even so, the postsurgery survival rate of patients is still extremely poor. Direct curative resection may benefit most patients. This study aimed to improve the prognosis predicting accuracy of the Child-Pugh scoring system. Methods: This study included two cohorts: cohort A being composed of 613 HCC patients, with a 23-month median postsurgery follow-up time; and cohort B being composed of 554 tumor-free chronic liver disease patients. Kaplan-Meier test and Cox model were used for survival analysis. Independent-samples t test or one-way ANOVA was used to test the differences between different groups. Results: Serum prealbumin levels were found inversely correlated with worsening of fibrotic scores (r = -0.482, p < 0.001). Lower levels of presurgery prealbumin was an independent factor of poor postsurgery prognosis in Child-Pugh A patients, with a hazard ratio of 0.731 (p = 0.001). By integrating prealbumin together with total bilirubin level, serum albumin concentration and prothrombin time, a modified liver disease prognosis scoring system was developed to define traditional Child-Pugh A HCC patients as Modified Child-Pugh MCP-1, MCP-2 and MCP-3, with median postsurgery overall survival times of 44.00, 28.00 and 11.00 months respectively. Conclusions: Preoperative serum prealbumin is a valuable prognosis predicting biomarker for Child-Pugh A HCC patients who may be under consideration for curative resection. With serum prealbumin included as one of the parameters, the MCP scoring system might improve the postsurgery survival predicting accuracy for HCC patients.
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OBJECTIVE: Several members of protocadherins (PCDHs) have been identified as tumor suppressor genes in human carcinogenesis, but little is known about PCDH19. The aim of the present study was to assess the expression and methylation of PCDH19 in hepatocellular carcinoma (HCC). METHODS: The RNA-seq data from The Cancer Genome Atlas Database were downloaded and used for analyzing PCDH19 expression in HCC patients and normal liver tissues. We collected 63 paired tumor and nontumor liver tissues from hepatitis B virus-related HCC patients. The expression of PCDH19 was detected by real-time quantitative RT-PCR assay. The methylation of PCDH19 gene was analyzed by DNA methylation-sensitive endonuclease digestion and the sequential quantitative PCR. The prognostic value of PCDH19 gene methylation was evaluated by Kaplan-Meier analyses. RESULTS: PCDH19 expression was downregulated in HCC tissues and seven HCC cell lines compared to nontumor tissues. PCHD19 promoter was frequently hypermethylated in three (SMMC7721, Hep3B and SNU387) of seven HCC cell lines and 5-aza-dC treatment could significantly increased the PCDH19 expression in these methylated cells. In addition, HCC tumor tissues exhibited significantly increased PCDH19 hypermethylation both in frequency (30.15% vs 9.52%, P = 0.003) and in intensity (P = 0.002) compared to that in nontumor tissues. Kaplan-Meier survival analysis revealed that PCDH19 hypermethylation was correlated with the poor overall survival of HCC patients. CONCLUSION: PCDH19 expression was downregulated in HCC, which was mediated at least in part by promoter hypermethylation. PCDH19 hypermethylation might present a potential prognostic marker in HCC patients.
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Biomarcadores de Tumor/genética , Cadherinas/genética , Carcinoma Hepatocelular/patología , Metilación de ADN , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Islas de CpG , Regulación hacia Abajo , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , ProtocadherinasRESUMEN
Serum Golgi protein 73 (GP73) is a promising marker for significant fibrosis in adults. However, current diagnostic value of serum GP73 for liver fibrosis in children is unknown. To investigate the relationship between levels of serum GP73 and liver fibrosis in children, we measured serum GP73 in 86 healthy controls and 183 patients with liver diseases using commercially available double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) kit. The value of serum GP73 in fibrosis stage assessment was compared with aspartate transaminase to platelet ratio index (APRI). We found that serum GP73 was decreasing with age in healthy controls, while it was increasing with the extent of inflammation and fibrosis in patients with liver diseases. Though area under the receiver operating curve (AUROC) of serum GP73 for diagnosing significant fibrosis was nearly equal to APRI (0.62 vs 0.64) in patients aged 3 years or older, AUROC for serum GP73 was superior to APRI (0.76 vs 0.67) in patients aged below 3 years, indicating that serum GP73 is comparable to APRI for diagnosing significant fibrosis in children.