Yu-Chen Fan

Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease

Transient elastography (TE), as a non‐invasive method, has been studied for evaluation of portal hypertension in patients with chronic liver diseases (CLD) with variable results. We studied the performance of TE for detection of significant portal hypertension, oesophageal varices and large oesophageal varices using meta‐analysis.

Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis

Evidences from randomized controlled trials (RCTs) for the efficiency of traditional Chinese medicine (TCM) on the treatment of nonalcoholic fatty liver disease (NAFLD) are conflicting. Here we conducted a systematic review and meta-analysis of RCTs to evaluate the efficiency and safety of TCM in the treatment of NAFLD. Studies were searched on PubMed and China National Knowledge Infrastructure from January 1995 to June 2010. RCTs comparing either TCM formulations alone or in combination with placebo, ursodeoxycholic acid, insulin sensitizers, lipid-lowering drugs, or antioxidants were included. The category of most usually used herbs in the treatment of NAFLD was also calculated. Five thousand nine hundred and four patients from 62 RCTs were included for meta-analysis and 25,661 patients from 419 clinical studies were for TCM formulation analysis. Comparing with western medicines mentioned above, TCM had a better effect on the normalization of alanine aminotransferase and disappearance of radiological steatosis in the treatment of NAFLD. Furthermore, 246 kinds of Chinese herbs were included in our present study, with an average of 10 herbs (range 1–31) in each formulation. Hawthorn Fruit (321 times in 17,670 patients) was the most often used herb in the treatment of NAFLD. In conclusion, TCM is of modest benefit to the treatment of NAFLD.

A model to predict 3-month mortality risk of acute-on-chronic hepatitis B liver failure using artificial neural network

Model for end‐stage liver disease (MELD) scoring was initiated using traditional statistical technique by assuming a linear relationship between clinical features, but most phenomena in a clinical situation are not linearly related. The aim of this study was to predict 3‐month mortality risk of acute‐on‐chronic hepatitis B liver failure (ACHBLF) on an individual patient level using an artificial neural network (ANN) system. The ANN model was built using data from 402 consecutive patients with ACHBLF. It was trained to predict 3‐month mortality by the data of 280 patients and validated by the remaining 122 patients. The area under the curve of receiver operating characteristic (AUROC) was calculated for ANN and MELD‐based scoring systems. The following variables age (P < 0.001), prothrombin activity (P < 0.001), serum sodium (P < 0.001), total bilirubin (P = 0.015), hepatitis B e antigen positivity rate (P < 0.001) and haemoglobin (P < 0.001) were significantly related to the prognosis of ACHBLF and were selected to build the ANN. The ANN performed significantly better than MELD‐based scoring systems both in the training cohort (AUROC = 0.869 vs 0.667, 0.591, 0.643, 0.571 and 0.577; P < 0.001, respectively) and in the validation cohort (AUROC = 0.765 vs 0.599, 0.563, 0.601, 0.521 and 0.540; P ≤ 0.006, respectively). Thus, the ANN model was shown to be more accurate in predicting 3‐month mortality of ACHBLF than MELD‐based scoring systems.

Glutathione S-Transferase P1 Correlated with Oxidative Stress in Hepatocellular Carcinoma

Background: Glutathione-S-transferase P1 (GSTP1) is an important phase II enzyme that can protect cells from oxidative stress in various human cancers. However, few clinical studies were undertaken on the relationship between GSTP1 and oxidative stress in hepatocellular carcinoma (HCC). The present study was therefore aimed to evaluate the potential associations between GSTP1 and oxidative stress in HCC patients. Methods: The GSTP1 expression in peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry from 38 HCC patients and 38 chronic hepatitis B (CHB) patients. The GSTP1 mRNA level in PBMCs was determined by real-time quantitative polymerase chain reaction. Enzyme-linked-immunosorbent-assay (ELISA) was performed to measure the oxidative stress status, including plasma levels of malondialdehyde (MDA), xanthine oxidase (XOD), reduced glutathione hormone (GSH) and glutathione-S-transferases (GST). Results: Significantly decreased GSTP1 protein expression was found in HCC patients than in CHB patients (P<0.05). The GSTP1 mRNA expression of HCC patients was also decreased compared with CHB patients (P<0.05). MDA and XOD levels were significantly higher in HCC patients than in CHB patients, while plasma GSH and GST levels were statistically lower in HCC patients than in CHB patients. GSTP1 expression level was correlated with plasma levels of MDA (P<0.01), XOD (P = 0.01) and GSH (P< 0.01), GST (P< 0.01). Conclusion: We demonstrated that the reduced GSTP1 expression might contribute to oxidative stress in the development of HCC from CHB.

Upper limits of normal for serum alanine aminotransferase levels in Chinese Han population.

Background and Objectives Serum alanine aminotransferase (ALT) activity is the most common tool for the assessment of liver diseases. However, it is not clear whether the current normal ALT range really discriminate patients with or without liver diseases. The present study was to establish a new normal range of ALT and examine its ability to identify patients with hepatitis B or nonalcoholic fatty liver disease (NAFLD) in Chinese Han population. Methods 53037 adults were included in this study from January 1st 2008 to August 31st 2010. The 95th percentile of ALT in population with relative low risk factors for liver diseases was set as the new upper limits of normal ALT in gender-specific manner. Results The 95th percentile levels at low risk factors for liver diseases were achieved at 35 U/L for men and 23 U/L for women. The concordance statistics for detection were 0.873 (95%CI: 0.865–0.881) for HBV and 0.932 (95%CI: 0.927–0.937) for NAFLD in men while 0.857 (95%CI: 0.850–0.864) for HBV and 0.909 (95%CI: 0.903–0.915) for NAFLD in women. The median sensitivity of the current used ALT upper limit (40 U/L) was 6.6% for HBV and 29.7% for NAFLD and median specificity was 98.7% for men and 99.4% for women. Using our new-derived thresholds, the sensitivities ranged from 35.3% to 61.1% and the specificities were 94.8% for men and 94.6% for women. Conclusions Our results suggest that upper limits of ALT 35 U/L for men and 23 U/L for women in Chinese Han population. Re-consideration of normal limits of ALT should be recommended. Trial Registration ChiCTR.org ChiCTR-OCS-11001173

Study on the function of circulating plasmacytoid dendritic cells in the immunoactive phase of patients with chronic genotype B and C HBV infection.

Summary.  Hepatitis B virus (HBV) infection induces a wide range of chronic liver injury. The mechanism by which HBV evades the immune surveillance system remains obscure. Plasmacytoid dendritic cells (pDCs) seem to be the major endogenous interferon (IFN)‐α producers and represent one of the most important cell types in the regulation of antiviral innate immunity; however, the phenotype and function of pDCs in patients infected by HBV with different genotypes are yet to be determined. The aim of this study was to investigate the differences in the numbers and function of peripheral blood pDCs in the immune clearing phase of chronic HBV infection with genotypes B and C. Fifty‐six patients with persistent HBV infection were included in this study, with 19 age‐matched healthy subjects being used as a control group. The frequencies of pDCs were analysed by flow cytometry, and the IFN‐α produced by peripheral blood mononuclear cells (PBMCs) after stimulation with cytidine phosphate guanosine (CpG) oligonucleotides for 24 h was determined by enzyme‐linked immunosorbent assay. The genotypes of HBV were detected by polymerase chain reaction and hybridization. The results showed that the frequency and IFN‐α‐producing capacity of peripheral blood pDCs were dramatically reduced and relatively inversely correlated with the level of serum alanine aminotransferase in both groups of patients with chronic genotype B and C HBV infection. A lower reduction of IFN‐α production by CpG‐stimulated PBMCs was found in patients with genotype C than in those with genotype B in the phase of immune clearance. In conclusion, the frequency and IFN‐α‐producing capacity of peripheral blood pDCs were dramatically reduced in the immunoactive phase of chronic hepatitis B (CHB). Furthermore, the lower reduction in IFN‐α production in patients with genotype C than in those with genotype B may correlate with the outcome of antiviral treatment in CHB patients and the progression of liver inflammation.

Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B Virus associated hepatocellular carcinoma.

Background: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients. Methods: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP). Results: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50. Conclusions: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.

Methylation of serum insulin‐like growth factor‐binding protein 7 promoter in hepatitis B virus‐associated hepatocellular carcinoma

Methylation of gene promoter CpG islands is an important early event in hepatocellular carcinoma (HCC), and detection of cell‐free tumor‐specific DNA methylation is becoming a useful noninvasive method for HCC. This study was aimed at determining the diagnostic value of serum insulin‐like growth factor‐binding protein 7 (IGFBP7) promoter methylation in hepatitis B virus‐associated HCC. A total of 217 subjects, including 136 HCC patients, 46 patients with chronic hepatitis B (CHB), and 35 healthy controls (HCs), were included. The methylation status of the serum IGFBP7 gene promoter was determined using methylation‐specific PCR. The frequency of serum IGFBP7 promoter methylation in HCC patients (89/136, 65%) was significantly higher than that in CHB patients (8/46, 17%; X2 = 31.883, P < 0.001) and HCs (5/35, 14%; X2 = 29.429, P < 0.001). Moreover, elevated IGFBP7 methylation frequency was also observed in HCC patients with vascular invasion compared with those without vascular invasion (84 versus 60%, X2 = 6.633, P = 0.010). The sensitivities of serum IGFBP7 methylation and alpha‐fetoprotein (AFP) in detecting HCC were 65 and 57%, respectively. Of note, the combination of IGFBP7 methylation and AFP showed 85% for sensitivity. These results suggest that methylation of the serum IGFBP7 gene promoter may serve as a useful noninvasive biomarker for HCC diagnosis.

Interleukin-28B polymorphisms on the SVR in the treatment of naïve chronic hepatitis C with pegylated interferon-α plus ribavirin: a meta-analysis.

There are accurate but inconclusive data on the association between single nucleotide polymorphisms (SNPs) of interleukin (IL)-28B and sustained virological response (SVR) in chronic hepatitis C (CHC). This meta-analysis aimed to derive a more precise estimation of the effects of IL-28B SNPs locus (rs12979860 and rs8099917) on SVR in naïve CHC patients receiving pegylated interferon alpha (PEG-IFN-α) plus ribavirin. Literature search was conducted up to June, 2011, in PubMed, EMBASE and Cochrane Database of Systematic Reviews. A total of 36 studies involving 10912 cases with CHC receiving PEG-IFN-α plus ribavirin met the inclusion criteria. Analyses were stratified either by ethnicity or genotype of hepatitis C virus. In genotype 1/4 patients, rs12979860 CC was associated with high SVR in CHC patients (Caucasian: odds ratio (OR), 4.567; 95% confidence interval (CI), 3.826-5.452; Asian: OR, 4.033; 95%CI, 3.050-5.333; African American: OR, 4.297; 95%CI, 2.168-8.515; Hispanics: OR, 4.350; 95%CI, 2.817-6.717) but had no effect in genotype 2/3. In Caucasian (genotype 1/4: OR, 2.542; 95%CI, 2.108-3.065; genotype 2/3: OR, 1.363; 95%CI, 1.020-1.820) and Asian (genotype 1/4: OR, 5.214; 95%CI, 3.694-7.360; genotype 2/3: OR, 1.785; 95%CI, 1.095-2.910), rs8099917 TT was associated with high SVR in both genotype 1/4 and 2/3. Meta-regression showed that in Caucasians with CHC genotype 1/4, gender male might contribute to the effect of rs12979860 on SVR but advanced fibrosis might weaken this effect. Furthermore, in Asians with CHC genotype 1/4, high baseline viral load and advanced fibrosis might also undermine the effect of rs8099917 on SVR. This meta-analysis suggested that IL-28B rs12979860 CC and rs8099917 TT were associated with high SVR rate in CHC genotype 1/4. In CHC genotype 2/3, rs8099917 TT carriers also had higher SVR.

Interleukin-28B rs12979860C/T and rs8099917T/G contribute to spontaneous clearance of hepatitis C virus in Caucasians.

Two single nucleotide polymorphisms rs12979860C/T and rs8099917T/G around interleukin-28B (IL28B) locus have been extensively investigated in their association with hepatitis C virus (HCV) spontaneous clearance. However, with the variable and even inconsistent results, it is necessary to conduct a meta-analysis. A literature search was conducted to seek articles about genetic variation of IL28B and spontaneous clearance of HCV. Odds ratio with 95% confidential interval were calculated to estimate their relationship. Furthermore, meta-regression analysis was performed to search for potential affective factors. A total of 8 studies including 2460 patients with chronic HCV infection and 1052 individuals with spontaneous HCV clearance met inclusion criteria, in which seven studies describing rs12979860 and three studies describing rs8099917. Analysis performed in Caucasian populations indicated that rs12979860CC and rs8099917TT contributed to HCV spontaneous clearance in both dominant model (CC vs. CT+TT, P<1×10(-4); TT vs. TG+GG, P<10(-4), respectively) and co-dominant model (CC vs. CT, P<1×10(-4), CC vs. TT, P<1×10(-4); TT vs. TG, P<10(-4), TT vs. GG, P=0.012, respectively). Meta-regression analysis suggested that male proportion (P=1×10(-5)) and mean age (P=1×10(-3)) might weaken the effect of rs12979860CC, but HCV genotype 1/4 (P=4×10(-4)) might contribute to it. IL28B rs12979860CC and rs8099917TT genotypes contribute to spontaneous HCV clearance in Caucasians.