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.

Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis.

BACKGROUND: NAFLD is tightly associated with various diseases such as diabetes, cardiovascular disease, kidney disease, and cancer. Previous studies had investigated the association between NAFLD and various extrahepatic cancers, but the available data to date is not conclusive. The aim of this study was to investigate the association between NAFLD and various extrahepatic cancers comprehensively. METHODS: Searches were conducted of various electronic databases (PubMed, EMBASE, Medline, and the Cochrane Library) to identify observational studies published between 1996 and January 2020 which investigated the association between NAFLD and extrahepatic cancers. The pooled OR/HR/IRR of the association between NAFLD and various extrahepatic cancers were analyzed. RESULTS: A total of 26 studies were included to investigate the association between NAFLD and various extrahepatic cancers. As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40-2.11) and 1.37 (95%CI: 1.29-1.46), respectively. The pooled OR values of the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in patients with NAFLD were 2.46 (95%CI: 1.77-3.44) and 2.24 (95%CI: 1.58-3.17), respectively. The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44-1.99). In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer. CONCLUSIONS: NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer. NAFLD could be considered as one of the influencing factors during the clinical diagnosis and treatment for the extrahepatic cancers.

TRIB1 rs17321515 gene polymorphism increases the risk of coronary heart disease in general population and non-alcoholic fatty liver disease patients in Chinese Han population.

BACKGROUND: Present evidences suggested that TRIB1 rs17321515 polymorphism was tightly associated with the increased risk of NAFLD and CHD. CHD is one of the main complications of NAFLD, whether TRIB1 rs17321515 polymorphism could affect the risk of CHD in general population and NAFLD patients in Chinese Han population was remain unknown. The present study was designed to investigate the association between TRIB1 rs17321515 polymorphism and the risk of CHD in general population and NAFLD patients in Chinese Han population, and investigate the effect of TRIB1 rs17321515 polymorphism on serum lipid levels. PATIENTS AND METHODS: TRIB1 rs17321515 gene polymorphism was genotyped using the polymerase chain reaction (PCR) in healthy controls (n = 175), CHD patients (n = 155), NAFLD patients (n = 146), and NAFLD+CHD patients (n = 156). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 24.0 statistical software. RESULTS: The TRIB1 rs17321515 AA+GA genotypes were the significant risk factors for the CHD in general population (OR = 1.788; 95% CI: 1.104-2.897; P = 0.018) and in the NAFLD patients (OR = 1.760; 95% CI: 1.071-2.891; P = 0.026). After adjusted for age, gender, and body mass index, the risk for CHD in general population (OR = 1.857; 95% CI: 1.116-3.089; P = 0.017) and NAFLD patients was still significant (OR = 1.723; 95% CI: 1.033-2.873; P = 0.037). In addition, TRIB1 rs17321515 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 AA+GA genotypes were significant associated with the risk of CHD in general population and in NAFLD patients in Chinese Han population. The rs17321515 A allele increases the serum lipid profiles in included subjects.

Role and effective therapeutic target of gut microbiota in NAFLD/NASH.

Non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease in the world, is affected by numerous extrinsic and intrinsic factors, including lifestyle, environment, diet, genetic susceptibility, metabolic syndrome and gut microbiota. Accumulating evidence has proven that gut dysbiosis is significantly associated with the development and progression of NAFLD, and several highly variable species in gut microbiota have been identified. The gut microbiota contributes to NAFLD by abnormal regulation of the liver-gut axis, gut microbial components and microbial metabolites, and affects the secretion of bile acids. Due to the key role of the gut microbiota in NAFLD, it has been regarded as a potential target for the pharmacological and clinical treatment of NAFLD. The present review provides a systematic summary of the characterization of gut microbiota and the significant association between the gut microbiota and NAFLD. The possible mechanisms of how the gut microbiota is involved in promoting the development and progression of NAFLD were also discussed. In addition, the potential therapeutic methods for NAFLD based on the gut microbiota were summarized.

TM6SF2 E167K Variant Overexpression Promotes Expression of Inflammatory Cytokines in the HCC Cell Line HEPA 1-6.

Background and Aims: Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma (HCC), and E167K variant of the transmembrane 6 superfamily member 2 (TM6SF2) plays an important role in the progression of chronic liver diseases and HCC. The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8 in the HCC cell line HEPA 1-6. Methods: HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wild-type, or control plasmids. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8. A t-test was used for statistical analysis. Results: Compared with the control group and TM6SF2 overexpression group, the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group (p < 0.05). The relative mRNA expression of IL-8 in the TM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group (p < 0.05). No obvious differences were observed for the expression of TNF-α in each group. The expression of TNF-α, IL-2, IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results. Conclusions: In conclusion, the E167K variant of the TM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells, suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.

Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis.

OBJECTIVE: To systematically review studies about the diagnostic accuracy of magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the classification of hepatic steatosis grade in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Areas under the summary receiver operating characteristic curves (AUROC), sensitivity, specificity, overall diagnostic odds ratio (DOR), diagnostic score, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) for MRI-PDFF in classification of steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were compared and analyzed. RESULTS: A total of 6 studies were included in this meta-analysis (n = 635). The summary AUROC values of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.98, 0.91, and 0.90, respectively. Pooled sensitivity and specificity of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.93 and 0.94, 0.74 and 0.90, and 0.74 and 0.87, respectively. Summary +LR and -LR of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 16.21 (95%CI, 4.72-55.67) and 0.08 (95%CI, 0.04-0.15), 7.19 (95%CI, 5.04-10.26) and 0.29 (95%CI, 0.22-0.38), and 5.89 (95%CI, 4.27-8.13) and 0.29 (95%CI, 0.21-0.41), respectively. CONCLUSIONS: Our meta-analysis suggests that MRI-PDFF has excellent diagnostic value for assessment of hepatic fat content and classification of histologic steatosis in patients with NAFLD. KEY POINTS: • MRI-PDFF has significant diagnostic value for hepatic steatosis in patients with NAFLD. • MRI-PDFF may be used to classify grade of hepatic steatosis with high sensitivity and specificity.

Apolipoprotein A5 gene polymorphisms are associated with non-alcoholic fatty liver disease.

BACKGROUND: Several studies have reported that apolipoprotein A5 (APOA5) is involved in the development of non-alcoholic fatty liver disease (NAFLD). However, no research has been performed regarding the association between APOA5 polymorphisms and the risk of NAFLD. This study aimed to explore the association between APOA5 gene polymorphisms and NAFLD in a Chinese Han population. METHODS: Genotypes of the SNPs (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 in 232 NAFLD patients and 188 healthy controls were determined using polymerase chain reaction (PCR) analysis. Clinical characteristics were measured using biochemical methods. RESULTS: The five single nucleotide polymorphisms (SNPs) (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 showed no significant association with NAFLD (P > 0.05). The rs10750097 with G allele showed a higher serum level of alkaline phosphatase (ALP) compared with C allele in overall series and NAFLD patients (P < 0.05). The rs1263173(A/A) carriers showed a higher level of glucose compared to the non-carriers in overall series (P < 0.05). The rs17120035(T/T) carriers showed a lower plasma TG level in overall series and NAFLD patients (P < 0.05), and the rs662799(G/G) carriers showed higher levels of plasma triglyceride (TG), ALP, and lower level of high-density lipoprotein (HDL) compared to non-carriers in NAFLD patients (P < 0.05). No significant difference were observed on the clinic parameters of APOA5 rs3135507(T/T) carriers in both group of overall series and NAFLD patients (P > 0.05). CONCLUSIONS: The five SNPs (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 gene are not associated with the risk of NAFLD in the Chinese Han population. The genotypes of rs10750097(G/G), rs1263173(A/A), rs17120035(T/T), and rs662799(G/G) performed a significant effect on clinic characteristics in overall series and NAFLD patients, indicating that these polymorphisms may be associated with NAFLD.

Association of serum ferritin with non-alcoholic fatty liver disease: a meta-analysis.

BACKGROUND: A growing number of studies reported the connection between the level of serum ferritin (SFL) and non-alcoholic fatty liver disease (NAFLD). However, such connection was still disputable. The aim of our meta-analysis was to estimate SFL between the groups as below: patients with NAFLD against control group; non-alcoholic steatohepatitis (NASH) patients against control group; non-alcoholic fatty liver (NAFL) patients against a control group and NASH patients vs NAFL patients. METHODS: We screened the studies in PubMed, EMBASE, the Cochrane Database and the Cochrane Central register controlled trials from the beginning to July 10, 2016 to find the studies indicated the connection between SFL and NAFLD (NAFL and/or NASH). Fourteen published studies which evaluate the SFL in NAFLD patients were selected. RESULTS: Higher SFL was noticed in NAFLD patients against control group (standardized mean difference [SMD] 1.01; 95% CI 0.89, 1.13), NASH patients against control group (SMD 1.21; 95% CI 1.00, 1.42), NAFL patients against control group (SMD 0.51; 95% CI 0.24, 0.79) and NASH patients against NAFL patients (SMD 0.63; 95% CI 0.52, 0.75). These results remained unaltered actually after the elimination of studies which were focused on paediatric or adolescent populations. Higher SFL was presented in NAFLD patients against the control group (SMD 1.08; 95% CI 0.95, 1.20) in adults and NASH patients against NAFL patients in adults (SMD 0.74; 95% CI 0.62, 0.87). The connection between SFL and NASH against NAFL group in paediatric or adolescent populations was observed inconsistently (SMD 0.10; 95% CI -0.18, 0.38). CONCLUSIONS: The level of SFL was elevated in patients with NAFLD (NAFL and/or NASH) compared with the controls. Compared with NAFL, The level of SFL was increased in NASH. The result remained unaltered actually after the elimination of studies focused on paediatric or adolescent populations.

The additive effects of the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism.

There is a genetic susceptibility for nonalcoholic fatty liver disease (NAFLD). To examine the role of genetic factors in the disease, a Bayesian analysis was performed to model gene relationships in NAFLD pathogenesis. The Bayesian analysis indicated a potential gene interaction between the TM6SF2 and PNPLA3 genes. Next, to explore the underlying mechanism at the cellular level, we evaluated the additive effects between the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism. Hepa 1-6 cells were transfected with a control vector or with overexpression vectors for TM6SF2/PNPLA3-wild type, TM6SF2-mutant type, PNPLA3-mutant type, or TM6SF2/PNPLA3-mutant type. Commercial kits were used to measure triglyceride and total cholesterol levels in each of the five groups. The mRNA and protein expression levels of sterol regulatory element-binding transcription factor 1c and fatty acid synthase were analyzed using real-time PCR and western blotting. The triglyceride and total cholesterol contents were significantly different among the groups. The triglyceride and total cholesterol contents and the sterol regulatory element-binding transcription factor 1c and fatty acid synthase mRNA and protein expression levels were significantly higher in the TM6SF2/PNPLA3-mutant type group than in the TM6SF2-mutant type group or the PNPLA3-mutant type group. The TM6SF2 E167K and PNPLA3 I148M polymorphisms may have additive effects on lipid metabolism by increasing the expression of sterol regulatory element-binding transcription factor 1c and fatty acid synthase.

E167K polymorphism of TM6SF2 gene affects cell cycle of hepatocellular carcinoma cell HEPA 1-6.

BACKGROUND: Some studties reported that the polymorphism of TM6SF2 gene E167K affects the occurrence and the progression of hepatocytes carcinoma (hepatocellular, HCC). In oeder to investigate the effects of the polymorphism of TM6SF2 gene E167K in the pathogenesis of HCC, we explored its influence on the cell cycle in hepatocellular carcinoma cell HEPA1-6. METHODS: HEPA 1-6 cells which could respectively overexpress TM6SF2 wild type and E167K variant were cultured and HEPA 1-6 cells with zero load plasmids were used as matched control. Flow cytometry was used to detect the cell cycles of these 3 type of HEPA 1-6 cells. Realtime fluores-cence quantitative PCR and western blot were used to analyzed the expression of regulatory factors (Cyclin D1、p53、P16、P27、P21 and Rb) of cell cycle. T-test was used in statistical analysis. RESULTS: Cell cycle phase distribution was presented by the proportion of cells in each phases (%). Compared with the control group, the cell cycle phase distribution (G1 phase 57.36 ± 0.21%, G2/M phase 25.61 ± 0.36%,S phases 19.31 ± 0.25%) had no differences in wild type group (G1 phase 57.63 ± 0.28%, G2/M phase 25.77 ± 0.51%, S phases 19.54 ± 0.25%; P < 0.05). Between variant type group and wild type group,G1 phase was significantly decreased (variant type group G1 phase 36.26 ± 0.31%, P < 0.05),S phase and G2/M phase were increased(variant type group S phase 28.41 ± 0.31%, P < 0.05;G2/M phase 35.23 ± 0.14%, P < 0.05), respectively. Compared with control group,the relative expression of CyclinD1、P53 and Rb mRNA in variant type group was significantly upregulated (2.03 ± 0.01 VS 1.04 ± 0.06, 1.88 ± 0.05 VS 1.37 ± 0.03, 1.29 ± 0.06 VS 1.15 ± 0.03, P < 0.05) and P27 mRNA in variant type group was significantly downregulated (0.56 ± 0.02 VS 0.85 ± 0.05, P < 0.05). Compared with wild type group, the relative expression of CyclinD1、P53 and Rb mRNA in variant type group was significantly upregulated (wild type group 1.00 ± 0.00, 1.48 ± 0.09, 1.18 ± 0.01, P < 0.05) and P27 mRNA in variant type group was significantly downregulated (variant type group 0.82 ± 0.05,P < 0.05). There was no statistical significance between wild type group and control group (P > 0.05). P16 and P21 expression showed no statistical sigtfificance in any of these three groups (P > 0.05). CONCLUSION: E167K polymorphism of TM6SF2 gene affects cell cycles of HEPA1-6 cells via up-regulating CyclinD1、P53 and Rb and down-regulating P27.

Association of Adiponectin Gene Polymorphisms With the Risk of Coronary Artery Disease in Patients With Nonalcoholic Fatty Liver Disease in a Chinese Han Population.

BACKGROUND: Cardiovascular events are an independent risk factor for nonalcoholic fatty liver disease (NAFLD), which is the leading cause of mortality in NAFLD patients. Several recent studies demonstrated that adiponectin (Ad) polymorphisms were involved in the progression of NAFLD and coronary artery disease (CAD). However, reports on the association between Ad polymorphisms and the risk of developing CAD in NAFLD patients are lacking in a Northern Han Chinese population. OBJECTIVES: The present study was designed to evaluate the association between Ad gene polymorphisms (rs266729 and rs2241766) and the risk of developing CAD in Northern Han Chinese patients with NAFLD. MATERIALS AND METHODS: In this case-control study, using the polymerase chain reaction (PCR), Adrs266729 and rs2241766 gene polymorphisms were genotyped in B-type ultrasonography-proven NAFLD patients, with (n = 246) or without (n = 247) CAD and in healthy controls (n = 304). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 17.0 statistical software. RESULTS: There were significant differences in the Adrs266729 G allele between the NAFLD patients with and without CAD (P < 0.05). In addition, there was a significant difference in the Adrs2241766 G allele of the NAFLD patients compared with that of the controls (P < 0.05). In the NAFLD CAD population, carriers of the G allele of Adrs266729 had higher serum triglycerides (TG), total cholesterol (TC), fasting plasma glucose (FPG), and low-density lipoprotein (LDL) levels and a lower Ad level than their noncarrier counterparts (P = 0.031, P = 0.034, P = 0.007, P < 0.001, and P < 0.001, respectively). NAFLD patients without CAD had higher TG and serum FPG values and a lower Ad level than their noncarrier counterparts (P = 0.014, P = 0.038, and P < 0.001, respectively). In the NAFLD patients with/without CAD, the carriers of the G allele of Adrs2241766 had higher TG levels (P = 0.039 and P = 0.042, respectively) than those of their noncarrier counterparts. CONCLUSIONS: In this Northern Chinese Han population, the Adrs266729 and rs2241766 G alleles were closely associated with the occurrence of NAFLD. However, only NAFLD patients who carried the Adrs266729 G allele had an increased risk of developing CAD.