Che-g Chan

The protective role of natural phytoalexin resveratrol on inflammation, fibrosis and regeneration in cholestatic liver injury

Liver injuries can trigger a cascade of inflammatory responses and as a result, initiate the process of hepatic regeneration and fibrogenesis. Resveratrol (RSV) has multiple health-promoting benefits. This study evaluated the potential protective effects and mechanism of RSV as related to cholestatic liver injury. RSV was given (4 mg/kg/day, i.p.) for either 3 days or 7 days after bile duct ligation (BDL) injury. RSV significantly reduced serum ALT, AST but not T-bil on Day 3. At this early stage of injury, RSV significantly reduced TNF-α and IL-6 mRNA and decreased the number of Kupffer cells (CD68(+) ) recruited in the injured liver. RSV decreased hepatic fibrosis and reduced collagen Iα1 and TIMP-1 mRNA on Day 7. At the later stages of injury, RSV increased the number of Ki67(+) hepatocytes indicating that RSV promoted hepatocyte proliferation. Additionally, it resulted in decreased expression of 4-hydroxynonenal and increased expression of the hepatocyte growth factor protein and mRNA in the RSV-treated BDL group. Meanwhile, RSV reduced the mortality rate of BDL mice. In conclusion, RSV attenuated inflammation and reduced Kupffer cells activation. RSV decreased fibrosis and promoted hepatocyte regeneration, which increased the survival of BDL mice. RSV was beneficial for the treatment of cholestatic liver injury.

Efficacy of non-selective β-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: A randomized controlled trial

BACKGROUND & AIMS Gastric variceal obturation (GVO) therapy is the current treatment of choice for gastric variceal bleeding (GVB). However, the efficacy of non-selective β-blockers (NSBB) in the secondary prevention of GVB is still debatable. This study aimed at evaluating the efficacy of additional NSBB to repeated GVO in the secondary prevention of GVB. METHODS From April 2007 to March 2011, 95 patients with GVB after primary hemostasis using GVO were enrolled. Repeated GVO were performed until GV eradication. Forty-eight and 47 patients were randomized into the GVO alone group (Group A) and the GVO+NSBB group (Group B), respectively. Primary outcomes in terms of re-bleeding and overall survival were analyzed by multivariate analysis. RESULTS After a mean follow-up of 18.10 months in group A, 26 patients bled and 20 died. In group B, 22 patients bled and 22 died after a mean follow-up of 20.29 months. The overall re-bleeding and survival rates analyzed by the Kaplan-Meier method were not different between the two groups (p=0.336 and 0.936, respectively). The model of end-stage liver disease (MELD) score and main portal vein thrombosis (MPT) were independent determinants of re-bleeding while MPT and re-bleeding were independent factors of mortality by time-dependent Cox-regression model. Asthenia was the most common adverse event and was higher in group B (p<0.001). CONCLUSIONS Adding NSBB therapy to repeated GVO provides no benefit for the secondary prevention of bleeding and mortality in patients with GVB.

Asymmetric dimethylarginine (ADMA) determines the improvement of hepatic endothelial dysfunction by vitamin E in cirrhotic rats

Hepatic endothelial dysfunction (HED), which is caused by decreased hepatic nitric oxide (NO) bioavailability and increased lipid peroxidation, contributes to portal hypertension, which is a characteristic of cirrhosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is involved in cirrhosis‐related HED and portal hypertension.

The role of hepatitis G virus infection in patients with acute posttransfusion hepatitis in Taiwan

BACKGROUND & AIMS Hepatitis G virus (HGV) has been recently identified as a new transfusion-transmissible agent. This study was performed to evaluate the role of HGV infection in patients with acute posttransfusion hepatitis in Taiwan. METHODS Sera from 63 patients with acute posttransfusion hepatitis and 61 patients with normal serum aminotransferase levels after transfusion were tested for HGV RNA by reverse-transcription polymerase chain reaction. RESULTS Six of the 63 patients (9.5%) with acute posttransfusion hepatitis were positive for HGV RNA in pretransfusion sera; 4 were superinfected with hepatitis C virus (HCV) after transfusion and 3 developed chronic hepatitis. Seven (12.3%) of the remaining 57 patients had acute posttransfusion HGV infection; 5 were coinfected with HCV and 2 infected with HGV alone. None with acute HGV infection alone developed chronic hepatitis, whereas 4 of 5 patients (80%) with acute HGV and HCV coinfection developed chronic hepatitis. The clinical course of acute HGV and HCV coinfection was similar to that of acute HCV infection alone. Four of 61 subjects (6.6%) with normal serum aminotransferase levels after transfusion were subclinically infected with HGV. CONCLUSIONS HGV infection accounted for 12.3% of acute posttransfusion hepatitis in Taiwan before anti-HCV screening of blood donors. The clinical course of acute posttransfusion HGV infection alone was relatively benign.

Lack of detrimental effects of nitric oxide inhibition in bile duct-ligated rats with hepatic encephalopathy.

Background  The pathogenetic mechanisms of hepatic encephalopathy (HE) are not fully understood. Vasodilatation induced by nitric oxide (NO) may be involved in the development of HE. There is no comprehensive data concerning the effects of NO inhibition on HE in chronic liver disease.

IL28B polymorphism correlates with active hepatitis in patients with HBeAg-negative chronic hepatitis B.

Background & Aims The clinical relevance of single nucleotide polymorphisms (SNPs) near the IL28B gene is controversial in patients with hepatitis B virus (HBV) infection. This study aimed to investigate the role of viral and host factors, including IL28B genotypes, in the natural course of chronic hepatitis B (CHB). Methods The study enrolled consecutive 115 treatment-naive CHB patients. HBV viral loads, genotypes, precore and basal core promotor mutations, serum hepatitis B surface antigen (HBsAg) and interferon-gamma inducible protein 10 (IP-10) levels as well as four SNPs of IL28B were determined. Serial alanine transaminase (ALT) levels in the previous one year before enrollment at an interval of three months were recorded. Factors associated with active hepatitis, defined as persistent ALT >2× upper limit of normal (ULN) or a peak ALT level >5× ULN, were evaluated. Results The prevalence of rs8105790 TT, rs12979860 CC, rs8099917 TT, and rs10853728 CC genotypes were 88.3%, 87.4%, 88.4% and 70.9%, respectively. In HBeAg-positive patients (n = 48), HBV viral load correlated with active hepatitis, while in HBeAg-negative patients (n = 67), rs10853728 CC genotype (p = 0.032) and a trend of higher IP-10 levels (p = 0.092) were associated with active hepatitis. In multivariate analysis, high viral load (HBV DNA >108 IU/mL, p = 0.042, odds ratio = 3.946) was significantly associated with HBeAg-positive hepatitis, whereas rs10853728 CC genotype (p = 0.019, odds ratio = 3.927) was the only independent factor associated with active hepatitis in HBeAg-negative population. Conclusions HBV viral load and IL28B rs10853728 CC genotype correlated with hepatitis activity in HBeAg-positive and HBeAg-negative CHB, respectively. Both viral and host factors play roles in disease activity during different phases of CHB.

Hepatic endothelin‐1 and endocannabinoids‐dependent effects of hyperleptinemia in nonalcoholic steatohepatitis‐cirrhotic rats

Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine‐choline‐deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin‐1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD‐Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin‐1, and an increased IHR were found to be associated with higher levels of hepatic endothelin‐1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin‐1 type A receptor (ETAR), activator protein‐1, transforming growth factor beta (TGF‐β)1, osteopontin, tumor necrosis factor alpha (TNF‐α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ETAR, OBRb and activator protein‐1 in HSCs. Conclusion: An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin‐1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats. (HEPATOLOGY 2012)

Comparative analysis of noninvasive models to predict early liver fibrosis in hepatitis B e Antigen-negative Chronic Hepatitis B.

Background Portal or bridging fibrosis is an indication for antiviral treatment in patients with chronic hepatitis B (CHB). An early marker predictive of liver fibrosis in hepatitis B e antigen (HBeAg)-negative CHB patients can alert clinicians to plan for treatment before disease progression. Goals To predict early and significant liver fibrosis (Ishak score ≥2) in HBeAg-negative CHB by validating several noninvasive markers derived from CHC. Study One hundred seventy-seven consecutive treatment-naive HBeAg-negative CHB patients who underwent liver biopsy were divided into a training group (n=121) and a validation group (n=56). Factors associated with liver fibrosis were analyzed. Results Multivariate analysis identified Loks model ≥0.87, cirrhosis discriminant score greater than 4, and positive alanine aminotransferase ratio platelet score as independent factors associated with liver fibrosis in the training group. The area under the receiver operating characteristic curve revealed that Loks model was better than cirrhosis discriminant score in predicting liver fibrosis in both the training and the validation groups. In patients with hepatitis B virus DNA greater than 2000 IU/mL or greater than 20,000 IU/mL, Loks model showed equal prediction value (area under the receiver operating characteristic curve 0.709 and 0.704, respectively). Loks model could also discriminate high and low hepatitis B virus DNA loads. In general, liver biopsy can be avoided in one-third (58 of 177) of patients by Loks model. Conclusions Loks model ≥0.87 can be an early marker of liver fibrosis in HBeAg-negative CHB patients. Loks model has clinical applications not only for CHC, but also for HBeAg-negative CHB.

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: A short-term, randomized, double-blind controlled, cross-over study with long-term follow up

Abstract In order to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of Chinese patients with primary biliary cirrhosis, a short‐term, randomized, double‐blind controlled, cross‐over study was done with long‐term follow up. In the first part of the study, 12 patients were randomly chosen to receive either UDCA 600 mg/day for 3 months followed by a placebo for 3 months or a placebo for 3 months followed by UDCA for 3 months. The clinical symptoms of pruritus improved when the patients were receiving UDCA but became worse when receiving a placebo. Mean serum levels of alkaline phosphatase (ALPase), γ‐glutamyl transferase (γ‐GT), total bilirubin, cholesterol, alanine aminotransferase (ALT) and aspartate aminotransferase all decreased below the baseline values when receiving UDCA treatment and all increased above the baseline values when receiving the placebo. The difference was statistically significant. In the second part of the study, 19 patients received long‐term UDCA treatment (mean 20 months). The clinical symptoms of pruritus improved in 90% of the pruritic patients. Serum levels of ALPase, γ‐GT and ALT fell significantly from the pretreatment values 6, 12 and from the mean 20 months after UDCA treatment. Serum levels of total bilirubin fell significantly 6 and 12 months after UDCA treatment but did not reach statistical significance at the last follow up. No patient lost antimitochondrial antibody and elevated immunoglobulin levels did not improve significantly, but the Mayo clinical risk score improved significantly after long‐term UDCA treatment. Treatment failure was noted in three patients: two patients in the histologic stage IV with clinical overt jaundice died of complications 4 and 5 months after UDCA treatment, respectively; another patient underwent a liver transplantation 1 year after the UDCA treatment due to progressive jaundice. No severe adverse reaction was noted during UDCA treatment, only one patient suffered from a mild allergic reaction. In conclusion, UDCA is safe and effective in the treatment of Chinese PBC patients in stages I—III.

Impact of body mass index and viral load on liver histology in hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND & AIMS The impact of overweight and obesity on chronic hepatitis B (CHB) is unclear. This study was to examine the relationship among body mass index, viral load and liver histology in HBeAg-negative CHB. METHODS The study retrospectively investigated 136 HBeAg-negative chronic hepatitis B patients who had undergone liver biopsies in Taiwan. Factors associated with significant liver histology were analyzed. Definitions of overweight and obesity for the Asian population were body mass index≥23 kg/m(2) and ≥25 kg/m(2), respectively. RESULTS The prevalence of overweight, obesity, and type 2 diabetes mellitus in the 136 patients were 22.8%, 52.2%, and 12.5%, respectively. Multivariate analysis identified obesity, AST>40 U/L, HBV DNA>20,000IU/mL and platelet count<150 × 10(9)/L as independent factors associated with significant liver fibrosis. Similarly, overweight/obesity, ALT>80 U/L, HBV DNA>1,000,000IU/mL, and platelet count<150 × 10(9)/L were independent predictors of significant hepatic necro-inflammation. By stratification, high BMI and high viral load patients had more advanced stage and grade of liver histology. CONCLUSIONS Body mass index and HBV viral loads may have synergistic effect on disease progression in HBeAg-negative CHB. Both controlling body weight and anti-viral therapy are important in the management of CHB.