Renal and bone side effects of long-term use of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate in patients with Hepatitis B: a network meta-analysis.

BACKGROUND: Nucleoside analogues are currently applied as a first-line treatment for chronic hepatitis B (CHB) patients. However, the long-term effects of this type of treatment on kidney and bone tissue need to be further investigated. METHODS: We conducted a search of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) for treatment of CHB patients through October 29, 2023. Side effects of the three drugs were compared. Standardized mean difference (SMD), 95% confidence interval (95%CI), and surface under the cumulative ranking curve (SUCRA) were reported for each outcome. Further subgroup analysis was conducted according to duration of administration. RESULTS: ETV and TAF exhibited less effect on estimated glomerular filtration rate (eGFR) than TDF (SMD = -3.60 (95%CI: -1.94 ~ -5.26) and SMD = -4.27 (95%CI: -2.62 ~ -5.93)). ETV also exhibited less effect on creatinine rise than TAF and TDF (SMD = -0.55 (95%CI: -0.09 ~ -1.01) and SMD = -0.61 (95%CI: -0.15 ~ -1.06)). Moreover, the effect of TAF on bone mineral density (BMD) was less than that of TDF (SMD = -0.02 (95%CI: -0.01 ~ -0.02)). The probabilities of the three drugs changing relevant indicators exhibited similar patterns: eGFR (TDF (100.0%) > ETV (41.2%) > TAF (8.8%)), creatinine (TDF (94.7%) > TAF (54.7%) > ETV (0.6%)), BMD (TDF (79.7%) > ETV (50.6%) > TAF (19.6%)), and blood phosphorus (TDF (90.6%) > TAF (49.8%) > ETV (9.7%)). After 6 and 24 months of treatment, no statistically significant difference in renal function or bone tissue was observed between ETV and TDF. However, greater adverse effects on renal function were observed for TDF than ETV at 60 months compared to 12 months. TDF also exhibited greater adverse effects on bone tissue than ETV at 36 months than at 12 months. CONCLUSIONS: Long-term administration of TDF has resulted in stronger adverse effects than TAF and ETV in regard to both renal function and bone tissue in CHB patients. The effect of TAF on creatinine increase was greater than ETV. The difference in side effects between ETV and TDF was independent of treatment duration.

Alfosbuvir plus Daclatasvir for Treatment of Chronic Hepatitis C Virus Infection in China.

INTRODUCTION: A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. METHODS: All patients received 600 mg alfosbuvir tablets plus 60 mg daclatasvir tablets once daily for 12 weeks. The primary endpoint was sustained virological response 12 weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. RESULTS: Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. CONCLUSIONS: Alfosbuvir plus daclatasvir for 12 weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. TRIAL REGISTRATION: ClinicalTrial.gov identifier, NCT04070235.

Development and validation of a machine learning-based model for varices screening in compensated cirrhosis (CHESS2001): an international multicenter study.

BACKGROUND AND AIMS: The prevalence of high-risk varices (HRV) is low among compensated cirrhotic patients undergoing EGD. Our study aimed to identify a novel machine learning (ML)-based model, named ML EGD, for ruling out HRV and avoiding unnecessary EGDs in patients with compensated cirrhosis. METHODS: An international cohort from 17 institutions from China, Singapore, and India were enrolled (CHESS2001). The variables with the top 3 importance scores (liver stiffness, platelet count, and total bilirubin) were selected by the Shapley additive explanation and input into a light gradient-boosting machine algorithm to develop ML EGD for identification of HRV. Furthermore, we built a web-based calculator for ML EGD, which is free with open access (http://www.pan-chess.cn/calculator/MLEGD_score). Unnecessary EGDs that were not performed and the rates of missed HRV were used to assess the efficacy and safety for varices screening. RESULTS: Of 2794 enrolled patients, 1283 patients formed a real-world cohort from 1 university hospital in China used to develop and internally validate the performance of ML EGD for varices screening. They were randomly assigned into the training (n = 1154) and validation (n = 129) cohorts with a ratio of 9:1. In the training cohort, ML EGD spared 607 (52.6%) unnecessary EGDs with a missed HRV rate of 3.6%. In the validation cohort, ML EGD spared 75 (58.1%) EGDs with a missed HRV rate of 1.4%. To externally test the performance of ML EGD, 966 patients from 14 university hospitals in China (test cohort 1) and 545 from 2 hospitals in Singapore and India (test cohort 2) comprised the 2 test cohorts. In test cohort 1, ML EGD spared 506 (52.4%) EGDs with a missed HRV rate of 2.8%. In test cohort 2, ML EGD spared 224 (41.1%) EGDs with a missed HRV rate of 3.1%. When compared with the Baveno VI criteria, ML EGD spared more screening EGDs in all cohorts (training cohort, 52.6% vs 29.4%; validation cohort, 58.1% vs 44.2%; test cohort 1, 52.4% vs 26.5%; test cohort 2, 41.1% vs 21.1%, respectively; P < .001). CONCLUSIONS: We identified a novel model based on liver stiffness, platelet count, and total bilirubin, named ML EGD, as a free web-based calculator. ML EGD could efficiently help rule out HRV and avoid unnecessary EGDs in patients with compensated cirrhosis. (Clinical trial registration number: NCT04307264.).

Serum 25-hydroxyvitamin D levels and the risk of non-alcoholic fatty liver: A two-sample Mendelian randomization study.

Background: Accumulated studies have shown that low expression of 25-hydroxyvitamin D [25(OH)D] was significantly associated with the risk of non-alcoholic fatty liver disease (NAFLD). However, the exact causality is still unknown. The aim of this study was to investigate whether levels of 25(OH)D are associated with risk of NAFLD, using a two-sample Mendelian randomization (MR). Methods: Data from a recent large vitamin D genome-wide association study (GWAS) on 417,580 Europeans were utilized, and the largest published histology-based NAFLD GWAS study (1,483 cases and 17,781 healthy controls) for genetic variants predicted to cause NAFLD were searched. All genetic datasets for the MR analyses were obtained using publicly available summary statistics based on individuals of European ancestry from the MR-Base and NHGRI-EBI GWAS Catalog database. Inverse-variance weighted (IVW) MR approach was used to estimate causal effects in the main analysis, complemented by 4 additional methods to control for pleiotropy. Sensitivity analyses were conducted to verify whether heterogeneity and pleiotropy can bias the MR results. Results: The MR analysis did not provide strong evidence for the causal association of circulating 25(OH)D with NAFLD by IVW method (OR = 0.746, 95%CI 0.517-1.078; P = 0.119). The results were consistent using four other MR methods. Sensitivity analysis using all different analytical approaches yielded similar results. There was no evidence for pleiotropy (MR-Egger intercept: -0.0003758, P = 0.970). The replication process also showed consistent results using IVW method (P = 0.710). Conclusion: This study indicates that serum 25(OH)D levels did not possess an obvious effect on the risk of NAFLD. The associations in previous studies may be due to residual confounding or reverse causation.

Chaetomorpha linum polysaccharides alleviate NAFLD in mice by enhancing the PPARα/CPT-1/MCAD signaling.

BACKGROUND: Green algae contain many polysaccharides. However, there is no information on whether Chaetomorpha linum polysaccharides (CLP) can modulate lipid and glucose metabolism. MATERIAL AND METHODS: CLP were extracted from chlorella and their components were characterized. Male C57BL/6 mice were randomized and provided with control chow as the control, or high fat diet (HFD) to induce nonalcoholic fatty liver disease (NAFLD). NAFLD mice were treated orally with water as the HFD group or with 50 or 150 mg/kg CLP daily for 10 weeks. The impact of CLP treatment on lipid and glucose metabolism and the PPARα signaling was examined by histology, Western blotting and biochemistry. RESULTS: CLP mainly contained arabinogalactan sulfate. Compared with the control, HFD feeding increased body weights, lipid droplet liver deposition and induced hyperlipidemia, liver functional impairment and glucose intolerance in mice. Treatment with CLP, particularly with a higher dose of CLP, limited the HFD-increased body weights and liver lipid droplet deposition, mitigated the HFD-induced hyperlipidemia and improved liver function and glucose tolerance in mice. Mechanistically, feeding with HFD dramatically decreased the expression of liver PPARα, CPT-1, and MCAD, but treatment with CLP enhanced their expression in a trend of dose-dependent in mice. CONCLUSIONS: These findings indicated that CLP treatment alleviated the gain in body weights, NAFLD, and glucose intolerance in mice after HFD feeding by enhancing the PPARα/CPT-1/MCAD signaling.

Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC.

Background and Aims: Generally acceptable prognostic models for hepatocellular carcinoma (HCC) are not available. This study aimed to establish a prognostic model for HCC by identifying immune-related differentially expressed genes (IR-DEGs) and to investigate the potential role of NR6A1 in the progression of HCC. Methods: Bioinformatics analysis using The Cancer Genome Atlas and ImmPort databases was used to identify IR-DEGs. Lasso Cox regression and multivariate Cox regression analysis were used to establish a prognostic model of HCC. Kaplan-Meier analysis and the receiver operating characteristic (ROC) curves were used to evaluate the performance of the prognostic model, which was further verified in the International Cancer Genome Consortium (ICGC) database. Gene set enrichment analysis was used to explore the potential pathways of NR6A1. Cell counting kit 8, colony formation, wound healing, and Transwell migration assays using Huh7 cells, and tumor formation models in nude mice were conducted. Results: A prognostic model established based on ten identified IR-DEGs including HSPA4, FABP6, MAPT, NDRG1, APLN, IL17D, LHB, SPP1, GLP1R, and NR6A1, effectively predicted the prognosis of HCC patients, was confirmed by the ROC curves and verified in ICGC database. NR6A1 expression was significantly up-regulated in HCC patients, and NR6A1 was significantly associated with a low survival rate. Gene set enrichment analysis showed the enrichment of cell cycle, mTOR, WNT, and ERBB signaling pathways in patients with high NR6A1 expression. NR6A1 promoted cell proliferation, invasiveness, migration, and malignant tumor formation and growth in vitro and in vivo. Conclusions: An effective prognostic model for HCC, based on a novel signature of 10 immune-related genes, was established. NR6A1 was up-regulated in HCC and was associated with a poor prognosis of HCC. NR6A1 promoted cell proliferation, migration, and growth of HCC, most likely through the cell cycle, mTOR, WNT, and ERBB signaling pathways.

MiR-146a-5p, targeting ErbB4, promotes 3T3-L1 preadipocyte differentiation through the ERK1/2/PPAR-γ signaling pathway.

BACKGROUND: MicroRNAs (MiRNAs) are known to participate in preadipocyte differentiation, but the manner in which miR-146a-5p participates in this process remains unclear. This study was performed to examine the participation of miR-146a-5p in 3T3-L1 cell differentiation. MATERIAL AND METHODS: miR-146a-5p expression was upregulated and down-regulated to examine effects on 3T3-L1 cell differentiation. Bioinformatics analysis was performed to predict its target genes, and the signaling pathway it regulates was identified by qRT-PCR and Western blotting. The expression of miR-146a-5p in epididymal adipose tissue from obese mice and in an obese mouse adipose cell model was examined by qRT-PCR. RESULTS: 3T3-L1 cells differentiated into mature adipocytes successfully, as verified by increased areas of intracellular lipid droplets and elevated expression of mature adipocyte markers, and these cells had elevated miR-146a-5p expression. The intracellular lipid droplet and triglyceride contents and the expression of mature adipocyte markers were significantly increased in miR-146a-5p-overexpressing 3T3-L1 cells and markedly decreased in miR-146a-5p-inhibited 3T3-L1 cells. ErbB4 was a predicted target gene of miR-146a-5p. In miR-146a-5p-overexpressing 3T3-L1 cells, ErbB4 expression and ERK1/2 phosphorylation were decreased and the expression of PPAR-γ was increased; the opposite was observed in miR-146a-5p-inhibited 3T3-L1 cells. In addition, miR-146a-5p expression was significantly increased in the mouse epididymal adipose tissue and adipose cell model. CONCLUSIONS: Upregulated miR-146a-5p expression was related to 3T3-L1 cell differentiation. MiR-146a-5p promoted 3T3-L1 cell differentiation by targeting ErbB4 and via the ERK1/2/PPAR-γ signaling pathway.

Association between the LRP5 rs556442 gene polymorphism and the risks of NAFLD and CHD in a Chinese Han population.

BACKGROUND: Multiple studies have demonstrated the involvement of low-density lipoprotein receptor-related protein 5 (LRP5) in metabolism-related diseases. This study explored the relationship between the LRP5 rs556442 gene polymorphism and the risks of non-alcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD) in a Chinese Han population. METHODS: This retrospective case-control study included 247 patients with NAFLD, 200 patients with CHD, 118 patients with both NAFLD and CHD, and 339 healthy controls from June 2018 to June 2019 at Qingdao Municipal Hospital. Basic information and clinical characteristics were collected for all subjects. The genotype and allele frequency of LRP5 rs556442 were determined. RESULTS: The genotype distributions of LRP5 rs556442 differed significantly between the CHD and NAFLD + CHD groups (P < 0.05). The LRP5 rs556442 GG genotype markedly promoted the risk of NAFLD in CHD patients [odds ratio (OR) = 2.857, 95% confidence interval (CI): 1.196-6.824, P = 0.018). After adjustment for sex, age, and body mass index (BMI), this association remained significant (OR = 3.252, 95% CI: 1.306-8.102, P = 0.011). In addition, the LRP5 rs556442 AA + AG genotype was associated with an increased BMI in obese NAFLD patients (OR = 1.526, 95% CI: 1.004-2.319, P = 0.048). However, after adjustment for sex and age, this association was no longer significant (OR = 1.504, 95% CI: 0.991-2.282, P = 0.055). CONCLUSIONS: This study found that the LRP5 rs556442 GG genotype increased the risk of NAFLD in CHD patients and AA + AG genotype may be associated with an increased BMI in obese NAFLD patients among a Chinese Han population. Trial registration ChiCTR, ChiCTR1800015426. Registered 28 March 2018-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=26239 .

DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD.

DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD.

Relationship of circulating total bilirubin, UDP-glucuronosyltransferases 1A1 and the development of non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: This study aimed to investigate the correlation of circulating total bilirubin (TB) and UGT1A1 with NAFLD in Chinese Han population. METHODS: 172 adults were enrolled from the Qingdao Municipal Hospital from May 2019 to October 2020. All individuals were examined with MRI-PDFF and divided into no steatosis, mild steatosis, moderate steatosis, and severe steatosis groups according to the MRI-PDFF values. The biochemical indexes and UGT1A1 were measured. RESULTS: There was no significant difference of circulating TB and UGT1A1 levels between NAFLD group and controls. In the moderate steatosis and severe steatosis groups, the circulating TB levels were higher than that in control group (all P < 0.05). In addition, circulating TB levels were weak positively associated with liver fat fraction in NAFLD patients (ρ = 0.205, P = 0.001). There was no significant correlation between circulating UGT1A1 levels with liver fat fraction in patients with NAFLD (ρ = 0.080, P = 0.179), but positively correlation was found in patients with severe steatosis (ρ = 0.305, P = 0.026). CONCLUSIONS: The circulating TB levels were significant high in patients with moderate and severe steatosis. Circulating TB levels were weakly associated with liver fat fraction in patients with NAFLD, and the circulating UGT1A1 levels were positively correlated with liver fat fraction in NAFLD patients with severe steatosis. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022744. Registered 24 April 2019 - Retrospectively registered, http://www.chictr.org.cn/edit.aspx?pid=38304&htm=4 .

Efficacy and safety of alfosbuvir plus daclatasvir in Chinese patients with hepatitis C virus genotypes 1, 2, 3, and 6 infection: An open-label, phase 2 study.

Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. Our previous studies indicated that alfosbuvir monotherapy was well-tolerated and druggable in healthy subjects and HCV-infected patients. Here, we evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV genotype 1, 2, 3 or 6. In this open-label study, patients with chronic HCV infection were randomly assigned with a 1:1:1 ratio to receive 12 weeks of daclatasvir 60 mg plus alfosbuvir at a dose of 400, 600 or 800 mg (Cohort A, B or C) daily. Randomization was stratified by HCV genotype and the presence or absence of cirrhosis at screening. The primary endpoint was a sustained virologic response 12 weeks after the end of treatment (SVR12). A total of 124 patients were enrolled in the study, all of whom were available for post-treatment week 12 assessments. SVR12 was achieved in 92.7% (38/41), 95.2% (40/42) and 100% (41/41) of patients in Cohort A, B and C respectively. The most common adverse events were hepatic steatosis, upper respiratory tract infection, hypercholesterolaemia, hypertriglyceridaemia, blood bilirubin increased, and total bile acids increased. There were no discontinuations due to adverse events, and no treatment-related serious adverse events were reported. Once-daily oral administration of alfosbuvir plus daclatasvir were highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3 or 6, suggesting this regimen could be a promising drug candidate for HCV treatment irrespective of genotype. (ClinicalTrials.gov number, NCT04070235).

A predictive model for the diagnosis of non-alcoholic fatty liver disease based on an integrated machine learning method.

Diagnostic markers for non-alcoholic fatty liver disease (NAFLD) are still needed for screening individuals at risk. In recent years, the machine learning method was used to search for the diagnostic markers of multiple diseases. In this study, we developed and validated a machine learning model to diagnose NAFLD using laboratory indicators. NAFLD patients and non-NAFLD controls were recruited in the training and validation cohorts. The laboratory indicators of the participants in the training cohort were collected, and six indicators including alanine aminotransferase/aspartate aminotransferase (ALT/AST), white blood cells (WBC), alpha-L-fucosidase (AFU), hemoglobin (Hb), triglycerides (TG) and gamma-glutamyl transpeptidase (GGT) were screened out with higher weights by an integrate machine learning method. The areas under the receiver operating characteristic curves (AUROCs) for the selected indicators using logistic regression (LR), random forest (RF) and support vector machine (SVM) were 0.814, 0.837 and 0.810, respectively. Then the binary logistic regression was used to construct the predictive model. What's more, the AUROC of the predicted model was 0.732 in the validation cohort of patients with NAFLD. And the combined AUROC of the six parameters was 0.716 in the mouse model fed with high-fat diet (HFD). In summary, we created a predictive model with six laboratory indicators for the diagnosis of NAFLD based on the machine learning method, which has the potential value for the diagnosis of the NAFLD.

Lipid-induced DRAM recruits STOM to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD.

The biogenesis and diagnostic value of exosomes in nonalcoholic fatty liver disease (NAFLD) are unclear. In this study, we revealed that the plasma exosome level was higher in patients with NAFLD than that in healthy controls. Damage-regulated autophagy modulator (DRAM) was identified as one of the genes related to exosome secretion in patients with NAFLD. Then, loss or knockdown of DRAM down-regulated exosome secretion from hepatic cells using a knockout mouse model and a knockdown cell model. DRAM knockout reversed high-fat diet­induced increase of secreted exosomes. Furthermore, DRAM knockdown inhibited fatty acid (FA)­induced lysosomal membrane permeabilization and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice. Last, FA-induced DRAM interacted with stomatin and promoted its lysosomal localization to enhance exosome secretion from hepatic cells. We revealed a DRAM-mediated mechanism for exosome secretion and provided the foundation for plasma exosomes as a potential biomarker for NAFLD.

Serum Resistin Levels in Adult Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Previous studies reported that serum resistin levels were remarkably changed in patients with nonalcoholic fatty liver disease (NAFLD) but the conclusions were inconsistent. The aim of this study was to investigate accurate serum resistin levels in adult patients with NAFLD. METHODS: A complete literature research was conducted in the PubMed, Embase, and Cochrane Library databases, and all the available studies up to 7 May 2020 were reviewed. The pooled standardized mean difference (SMD) values were calculated to investigate the serum resistin levels in patients with NAFLD and healthy controls. RESULTS: A total of 28 studies were included to investigate the serum resistin levels in patients with NAFLD. Patients with NAFLD had higher serum resistin levels than controls (SMD=0.522, 95% confidence interval [CI]: 0.004-1.040, I 2=95.9%). Patients with nonalcoholic steatohepatitis (NASH) had lower serum resistin levels than the healthy controls (SMD=-0.44, 95% CI: -0.83-0.55, I 2=74.5%). In addition, no significant difference of serum resistin levels was observed between patients with NAFL and healthy controls (SMD=-0.34, 95% CI: -0.91-0.23, I 2=79.6%) and between patients with NAFL and NASH (SMD=0.15, 95% CI: -0.06-0.36, I 2=0.00%). Furthermore, subgroup and sensitivity analyses suggested that heterogeneity did not affect the results of meta-analysis. CONCLUSIONS: This meta-analysis investigated the serum resistin levels in adult patients with NAFLD comprehensively. Patients with NAFLD had higher serum resistin levels and patients with NASH had lower serum resistin levels than healthy controls. Serum resistin could serve as a potential biomarker to predict the development risk of NAFLD.

Tenofovir Alafenamide Fumarate, Tenofovir Disoproxil Fumarate and Entecavir: Which is the Most Effective Drug for Chronic Hepatitis B? A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: The therapeutic effect of tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir (ETV) on chronic hepatitis B (CHB) patients remains inconsistent. The aim of this study was to explore the differences in virological responses to TAF, TDF and ETV in patients with CHB. METHODS: Literature searches were conducted of the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials and observational studies published up to July 21, 2020. Statistical comparisons of virological response between TDF, ETV, and TAF were carried out with pooled odds ratio (OR) values. RESULTS: The virological response in TDF-treated CHB patients was notably superior to that of the ETV-treated CHB patients after 12-weeks [OR=1.12, 95% confidence interval (CI): 0.89-1.41], 24-weeks (OR=1.33, 95% CI: 1.11-1.61), 48-weeks (OR=1.62, 95% CI: 1.16-2.25), 72-weeks (OR=1.43, 95% CI: 0.78-2.62), and 96-weeks (OR=1.56, 95% CI: 0.87-2.81) treatment. No significant difference was observed for the virological responses in CHB patients after 48-weeks treatment with TAF or TDF. The virological response in TDF+ETV-treated CHB patients was superior to that of TDF-treated CHB patients after 24-weeks, 48-weeks (OR=1.54, 95% CI: 1.17-2.02), 96-weeks, and 144-weeks. CONCLUSIONS: The virological response in TDF-treated CHB patients was superior to that in ETV-treated CHB patients, but there was no significant difference between TAF and TDF. In addition, the therapeutic effect of TDF+ETV was superior to TDF alone.

Relationship between AGT rs2493132 polymorphism and the risk of coronary artery disease in patients with NAFLD in the Chinese Han population.

OBJECTIVE: To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. METHODS: Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. RESULTS: The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. CONCLUSIONS: The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.

Association of LDLR rs1433099 with the Risk of NAFLD and CVD in Chinese Han Population.

BACKGROUND AND AIMS: Recent genome-wide association studies have shown that low-density lipoprotein receptor (LDLR) rs1433099 polymorphism is associated with cardiovascular disease (CVD) risk in many countries. However, the association of LDLR rs1433099 with CVD in China has not been reported yet. There are no studies on LDLR rs1433099 and non-alcoholic fatty liver disease (NAFLD) as well. The purpose of this study was to investigate whether LDLR rs1433099 is related to CVD or NAFLD in the Chinese population. METHODS: LDLR rs1433099 polymorphism was genotyped in 507 individuals, including 140 healthy controls, 79 NAFLD patients, 185 CVD patients, and 103 patients with NAFLD combined with CVD. The expression of LDLR was tested by the sequence detection system, and clinical parameters were assessed by biochemical tests and physical examination. RESULTS: The genotype distribution of LDLR rs1433099 was not statistically different among the NAFLD group, the CVD group, the combined group, and the healthy control group (p>0.05). There was no significant correlation of LDLR rs1433099 genotypic distribution or allele frequency and the risk of NAFLD, CVD or NAFLD combined with CVD (p>0.05). In the CVD group, T allele carriers had higher alkaline phosphatase and gamma-glutamyl transpeptidase than non-carriers (p<0.05). CONCLUSIONS: Our study demonstrated that the LDLR rs1433099 polymorphism is not a risk factor of NAFLD. The LDLR rs1433099 polymorphism may increase the risk of CVD through a mechanism involving alkaline phosphatase and gamma-glutamyl transpeptidase.

Systematic Review and Meta-analysis of Circulating Fetuin-A Levels in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Accumulated studies have reported the key role of circulating fetuin-A in the development and progression of nonalcoholic fatty liver disease (NAFLD) but the results have not been consistent. In this study, we performed a systematic review and meta-analysis to explore the relationship between circulating fetuin-A level and the development and classification of NAFLD. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched to obtain the potentially relevant studies up to May 2020. Standardized mean differences (SMD) and 95% confidence intervals of circulating fetuin-A levels were extracted and summarized. Sensitivity, subgroup analysis and meta-regression analysis were performed to investigate the potential heterogeneity. Association of circulating fetuin-A level with classification of NAFLD was also reviewed. RESULTS: A total of 17 studies were included, composed of 1,755 NAFLD patients and 2,010 healthy controls. Meta-analysis results showed that NAFLD patients had higher circulating fetuin-A level (SMD=0.43, 95% confidence interval [CI]: 0.22-0.63, p<0.001) than controls. Subgroup analysis indicated that circulating fetuin-A level was markedly increased in adult NAFLD patients (SMD=0.48, 95% CI: 0.24-0.72, p<0.001) and not in pediatric/adolescent patients compared to controls. Circulating fetuin-A level was markedly increased in ultrasound-proven NAFLD pediatric/adolescent patients (SMD=0.42, 95% CI: 0.12-0.72, p=0.007), other than in the liver biopsy-proven NAFLD pediatric/adolescent patients. Body mass index might be the influencing factor to the heterogeneity in adult patients. Circulating fetuin-A level was not associated with the classification of NAFL vs. nonalcoholic steatohepatitis (NASH). Whether the circulating fetuin-A level was associated with the development of fibrosis remains controversial. CONCLUSIONS: Circulating fetuin-A level was significantly higher in NAFLD patients and was not associated with the classification of NAFL vs. NASH. Whether the circulating fetuin-A level was associated with the development of fibrosis remains controversial.

Diagnostic accuracy assessment of molecular prediction model for the risk of NAFLD based on MRI-PDFF diagnosed Chinese Han population.

BACKGROUND: Several molecular prediction models based on the clinical parameters had been constructed to predict and diagnosis the risk of NAFLD, but the accuracy of these molecular prediction models remains need to be verified based on the most accurate NAFLD diagnostic method. The aim of this study was to verify the accuracy of three molecular prediction models Fatty liver index (FLI), NAFLD liver fat score system (NAFLD LFS), and Liver fat (%) in the prediction and diagnosis of NAFLD in MRI-PDFF diagnosed Chinese Han population. PATIENTS AND METHODS: MRI-PDFF was used to diagnose the hepatic steatosis of all the subjects. Information such as name, age, lifestyle, and major medical histories were collected and the clinical parameters were measured by the standard clinical laboratory techniques. The cut-off values of each model for the risk of NAFLD were calculated based on the MRI-PDFF results. All data were analyzed using the statistical analysis software SPSS 23.0. RESULTS: A total of 169 subjects were recruited with the matched sex and age. The ROC curves of FLI, NAFLD LFS, and Liver fat (%) models were plotted based on the results of MRI-PDFF. We founded that the accuracy of FLI, NAFLD LFS, and Liver fat (%) models for the prediction and diagnosis of NAFLD were comparative available in Chinese Han population as well as the validity of them in other ethnics and regions. CONCLUSIONS: The molecular prediction models FLI, NAFLD LFS, and Liver fat (%) were comparative available for the prediction and diagnosis of NAFLD in Chinese Han population. MRI-PDFF could be used as the golden standard to develop the new molecular prediction models for the prediction and diagnosis of NAFLD.

Seraprevir and sofosbuvir for treatment of chronic hepatitis C virus infection: A single-arm, open-label, phase 3 trial.

BACKGROUND AND AIM: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. METHODS: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). RESULTS: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. CONCLUSIONS: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.