Propensity score matching-based analysis of the effect of corticosteroids in treating severe drug-induced liver injury.

BACKGROUND AND AIM: There is no conventional treatment for patients with severe drug-induced liver injury (DILI) except for discontinuation of liver injury drugs and symptomatic supportive therapy. Opinions on whether corticosteroids can be used to treat severe DILI are conflicting, and most of the relevant clinical studies are case reports or retrospective studies, which still need to be supported by high-level evidence-based medical studies. This study aimed to evaluate the effect and tolerance of corticosteroids in patients with severe DILI. Risk factors associated with patient failure to cure were also explored. METHODS: Propensity score matching based on nearest-neighbor 1:1 matching was used to screen severe DILI patients in the corticosteroids and control groups. Severe DILI was defined as elevated serum ALT and/or ALP with TBIL≥5 ULN (5 mg/dL or 85.5 µmol/L) with or without INR ≥1.5. Patients were treated with conventional therapy combined with corticosteroids in the corticosteroids group and only conventional therapy in the control group. RESULTS: A total of 146 patients, 73 each in the corticosteroids and control groups, were included in this study. By analyzing the entire cohort, we found no significant difference in cure rates between patients in the corticosteroid group and control group (34.2% vs. 20.5 %, p = 0.095), and there was no significant difference in the incidence of adverse effects between the two groups (20.5% vs. 20.5 %, p = 1.000). However, TBIL decreased more in the corticosteroids group on day 7 (89.2 ± 107.6 µmol/L vs. 58.8 ± 70.7 µmol/L, p = 0.046). In subgroup analyses, patients whose TBIL remained elevated despite conventional treatment had a higher TBIL decline on day 7,14 after use of corticosteroid (99.2 ± 98.5µmol/L vs. -23.3 ± 50.4µmol/L, p < 0.001; 120 ± 119.1µmol/L vs. 61.2 ± 98.5µmol/L, p = 0.047). The cure rate of patients in the corticosteroid group was significantly higher than that of the control group (36.1 % versus 4.5 %, p = 0.016). The proportion of patients with TBIL <85.5 µmol/L was also significantly higher in the corticosteroid group than in the control group at day 7 (p = 0.016) and day 14 (p = 0.004) after treatment. In the subgroup analysis of patients with different clinical phenotypes, the causative agent was herbal, autoimmune antibody-positive and 40 % < PTA ≤ 50 % of patients, corticosteroid use did not increase the cure rate of the patients. Univariate and multifactorial analyses found corticosteroid use to be a protective factor for failure to cure in patients with severe DILI (p < 0.001, OR:0.191,95 % CI:0.072-0.470), and peak TBIL to be a risk factor (p = 0.003, OR:1.016,95 % CI:1.007-1.028). CONCLUSIONS: The addition of corticosteroids could not increase the cure rate in patients with severe DILI, but it could rapidly reduce the patient's TBIL at an earlier stage. Corticosteroids could also promote curing in patients with elevated TBIL after conventional treatment. Corticosteroid use was a protective factor for failure to cure in patients with severe DILI and peak TBIL was a risk factor.

Ascites re-compensation in HBV-related first decompensated cirrhosis after anti-viral therapy.

Effective antiviral therapy can significantly improve the long-term prognosis of HBV-related decompensated patients, and re-compensation may be achieved in part of the patients. To explore the re-compensation of ascites after HBV suppression and the risk factors, the clinical outcomes of 196 consecutive patients with HBV-related first decompensated cirrhosis of ascites treated with nucleos(t)ide analogue (NUC) were analyzed retrospectively. Among these patients, the median serum HBV DNA level was 5.0 (IQR, 3.0-6.0) log10 IU/mL before treatment. Most patients were given NUC with high barrier to resistance including ETV (152), TDF (1) and TAF (1). Initial combination of LAM plus ADV and LdT plus ADV was used in 41 patients and 1 patients, respectively. After NUC treatment, the percentage of patients with ascites regression was 77.6%, 81.4%, 70.5%, 93.8%, 80.8% at 12, 24, 36, 48, 60 months, respectively (P<0.001). The distribution of ascites severity showed that the patients' ascites improved, with the proportion of no ascites and mild ascites gradually increased. The proportion of re-compensation of ascites defined as negative HBV DNA, improved liver function and ascites regression (off diuretics) was 59.7%, 70.0%, 52.3%, 59.4%, 46.2% at 12, 24, 36, 48, 60 months (P<0.001). The rate of ascites regression was higher in viral response (VR) cohort when compared with that in non-VR cohort. Univariate and multivariable analysis showed that level of serum ALT (OR:0.988, 95%CI, p=0.029) and load of serum HBV DNA (OR:0.78895%CI, p=0.044) at baseline were risk factors of re-compensation of ascites. This study demonstrated that antiviral therapy could reverse decompensation of ascites in HBV-related first decompensated cirrhosis and the level of ALT and HBV DNA were risk factors of ascites re-compensation.

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study.

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case-control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-ß (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69-11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08-10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49-10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25-1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25-1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01-13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14-82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00-18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.

Red Cell Distribution Width as a Prognostic Factor in Patients with Hepatocellular Carcinoma.

BACKGROUND: The red blood cell distribution width (RDW) was reported to be related to the severity of liver diseases, but its clinical significance in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to explore the clinical significance of RDW in HCC patients. METHODS: For the retrospective study, 422 HCC patients were enrolled in this study. Hematological parameters and liver biochemical indexes were analyzed. Child-Pugh grade and Barcelona Clinic Liver Cancer (BCLC) stages of the HCC patients were calculated. The diagnostic accuracy was evaluated according to the area under the receiver operating characteristic (ROC) curve. The medical records of HCC patients who were admitted to The Second Affiliated Hospital of Nanjing University of Chinese Medicine from January 2006 to August 2015 were retro-spectively reviewed. RESULTS: Subgroup analysis showed that RDW level of HCC patients with tumor size more than 10 cm were higher than those of HCC patients with tumor size smaller than 3 cm, 3 - 5 cm, and 5 - 10 cm (14.77 ± 2.35%, 15.27 ± 2.65%, 15.32 ± 2.40% vs. 15.97 ± 2.39%, p < 0.001). RDW level significantly increased with worsening Child-Pugh grade and BCLC stages. In addition, RDW level were negatively correlated with red blood cell (RBC) counts, hematocrit (HCT), lymphocyte (LY) counts, hemoglobin (Hb), blood platelet (PLT) counts, and positively correlated with aspartate-aminotransferase (AST), and total bile acid (TBA). ROC curve analysis showed that RDW level was 14.15% was the optimal prognostic cutoff point to determine the survival rate of HCC patients. In the univariate analysis followed by multivariate analysis, RDW level below 14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor size were prognostic indicators for HCC patients. This indicated HCC patients with RDW level below 14.15% [hazard ratio of 0.530 (95% confidence interval, 0.395 - 0.710; p < 0.001)] had the lower mortality. CONCLUSIONS: RDW level was positively associated with tumor size. The prognosis was better for HCC patients with RDW levels below14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor lesions. It suggested RDW level might be an easily obtainable and inexpensive prognostic indicator for HCC patients.

NDRG3 overexpression is associated with a poor prognosis in patients with hepatocellular carcinoma.

N-myc downstream-regulated gene 3 (NDRG3), an important member of the NDRG family, is involved in cell proliferation, differentiation, and other biological processes. The present study analyzed NDRG3 expression in hepatocellular carcinoma (HCC) and explored the relationship between expression of NDRG3 in HCC patients and their clinicopathological characteristics. We performed quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry (IHC) analyses on HCC tissues to elucidate NDRG3 expression characteristics in HCC patients. Kaplan-Meier survival curve and Cox regression analyses were used to evaluate the prognoses of 102 patients with HCC. The results revealed that compared with non-tumor tissues, HCC tissues showed significantly higher NDRG3 expression. In addition, our analyses showed that NDRG3 expression was statistically associated with tumor size (P=0.048) and pathological grade (P=0.001). Survival analysis and Kaplan-Meier curves revealed that NDRG3 expression is an independent prognostic indicator for disease-free survival (P=0.002) and overall survival (P=0.005) in HCC patients. The data indicate that NDRG3 expression may be considered as a oncogenic biomarker and a novel predictor for HCC prognosis.

Sperm-Associated Antigen 5 Expression Is Increased in Hepatocellular Carcinoma and Indicates Poor Prognosis.

BACKGROUND Sperm-associated antigen 5 (SPAG5), a gene that encodes a mitotic spindle-associated protein, is closely related to tumor development and is involved in cell migration and proliferation. The objective of this research was to explore the clinical significance of SPAG5 expression in hepatocellular carcinoma (HCC) and the relationship between SPAG5 expression and HCC prognosis. MATERIAL AND METHODS Twenty pairs of fresh-frozen HCC samples and samples from 95 HCC patients in a tissue microarray were subjected to quantitative real-time reverse-transcription (qRT)-PCR and immunohistochemistry (IHC), respectively, to investigate the relationship between the expression of SPAG5 and the clinicopathological features of HCC patients. RESULTS PCR data showed that the messenger RNA (mRNA) expression level of SPAG5 in HCC tissue specimens was higher than that in adjacent non-tumor tissue specimens (p<0.05). IHC analyses demonstrated that SPAG5 expression was significantly correlated with tumor grade (p=0.003), tumor number (p=0.009), vascular invasion (p=0.001), and TNM stage (p=0.001). Survival analysis and Kaplan-Meier curves showed that SPAG5 expression is an independent prognostic indicator for disease-free survival (p=0.017) and overall survival (p=0.016) in HCC patients. CONCLUSIONS Our results indicate that SPAG5 expression may be considered as an oncogenic biomarker and a novel predictor for HCC prognosis.

Elevated CTSL2 expression is associated with an adverse prognosis in hepatocellular carcinoma.

OBJECTIVE: Cathepsin V, also known as CTSL2, plays an important role in tumor development and progression. This study was designed to investigate the clinical significance of CTSL2 expression in hepatocellular carcinoma (HCC) and the relationship between CTSL2 expression and prognosis. METHODS: Quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were performed to determine the levels of CTSL2 mRNA and protein, respectively, in tumor tissue and matched non-tumor (NT) tissue. Moreover, the relationship between CTSL2 expression and hepatocellular carcinoma's clinicopathological features and survival was evaluated in HCC tissue. RESULTS: The levels of CTSL2 mRNA and protein were increased in HCC tissue. Moreover, for HCC patients, a high level of CTSL2 protein was significantly correlated with tumor number (P = 0.008), pathological grade (P = 0.001), vascular invasion (P = 0.001), T (P = 0.001), and TNM stage (P = 0.006). A Kaplan-Meier analysis showed that elevated CTSL2 expression was correlated with shorter disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Furthermore, a multivariate analysis showed that CTSL2 expression was an independent prognostic factor for DFS (P = 0.032) and OS (P = 0.025). CONCLUSION: This study showed that abnormal CTSL2 expression may contribute to HCC progression and that elevated CTSL2 expression is associated with an adverse prognosis in HCC.

The Value of GPC3 and GP73 in Clinical Diagnosis of Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has increased over the past decades in China. Current screening methods of HCC such as detection of α-fetoprotein (AFP) combined with liver ultrasonography remain unsatisfactory. Many HCC patients have already missed the optimal treatment period when diagnosed. Our study aimed to evaluate the value of Glypican 3 (GPC3) and Golgi protein 73 (GP73) in the detection of HCC. METHODS: Thirty-nine patients with HCC and 31 patients with liver cirrhosis were enrolled. The level of serum GPC3 and GP73 were determined by ELISA. The expression of GPC3 mRNA and GP73 mRNA in peripheral blood mononuclear cell (PBMC) and liver tissues were also measured with qRT-PCR. Then, receiving operating characteristic (ROC) curves were plotted to detect the sensitivity and specificity of serum GPC3 and GP73 in the diagnosis of HCC. RESULTS: The levels of serum GPC3 and GP73 in the HCC group were significantly higher than in the cirrhosis group (p < 0.0001). Patients with GPC3 > 9.3 µg/L and GP73 > 77.68 ng/mL had a risk of HCC of 92.31%. The HCC diagnosis ROC curve analysis indicated that when setting the GPC3 cutoff value > 9.3 µg/L, AUC = 0.956. The sensitivity and specificity of GPC3 were 89.74% and 96.77%, respectively, with a positive predictive value of 97.2%, negative predictive value of 88.2%, + LR of 27.82 and - LR of 0.11. When setting GP73 cutoff value > 77.68 ng/mL, AUC = 0.937. The sensitivity and specificity of GP73 were 92.31% and 83.87%, respectively, with positive predictive value of 87.8%, negative predictive value of 89.7%, + LR of 5.72 and - LR of 0.092. No significant difference (p > 0.05) was found between GPC3 and GP73 AUC in ROC curves, indicating that these two biomarkers were equivalent in the prediction of HCC. CONCLUSIONS: The expression of serum GPC3 and GP73 was significantly higher in the HCC patients compared with the cirrhosis patients. GPC3 and GP73 might be effective non-invasive diagnostic indicators of HCC.