Shinn-Jang Hwang

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis.

Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis and hepatocellular carcinoma. HCV NS5A, one of non-structural proteins of HCV, was suggested to play a role in oncogenic transformation. Since the tumor suppressor p53 is important for preventing neoplastic transformation, we investigated the functional effects of HCV NS5A on p53. In vitro and in vivo coimmunoprecipitation and confocal microscopy were used to determine the interaction of NS5A and p53. HCV NS5A binds directly to p53 and colocalizes p53 in the perinuclear region. NS5A inhibits transcriptional transactivation by p53 in a dose-dependent manner by use of a reporter assay. Down regulation of endogenous p21/waf1 expression, which is activated by p53 in Hep3B cells, by NS5A was demonstrated by using FLAG- and FLAG-NS5A Hep3B stable cell lines. The effect of NS5A on p53-mediated apoptosis was determined by flow cytometry in both NS5A permanently and transiently transfected Hep3B cells with exogenous p53. The p53-induced apoptosis was abrogated by NS5A and the inhibition effect correlates well with the binding ability of NS5A to p53. In addition, HCV NS5A protein interacts with and colocalizes hTAFII32, a component of TFIID and an essential coactivator of p53, in vivo. These results suggest that HCV NS5A interacts with and partially sequestrates p53 and hTAFII32 in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection.

Hepatic steatosis in chronic hepatitis C virus infection: Prevalence and clinical correlation

Background and Aims: Hepatic steatosis is a histological characteristic in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to evaluate the prevalence of hepatic steatosis in Chinese patients with chronic hepatitis C, and to look for possible correlation with various histopathological changes and to look for possible correlation with various clinical and pathologic variables.

The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding

Objectives:Cirrhotic patients with upper gastrointestinal bleeding are prone to bacterial infection. The aim of this study was to investigate the efficacy of prophylactic intestinal decontamination with oral ciprofloxacin for the prevention of bacterial infections in cirrhotic patients with upper gastrointestinal bleeding.Methods:A total of 120 cirrhotic patients with acute upper gastrointestinal bleeding were enrolled. Sixty patients received ciprofloxacin 500 mg twice daily given orally or through nasogastric tube immediately after upper gastrointestinal endoscopic examination; drug administration continued for 7 days. The remaining 60 patients, who received placebo, served as controls.Results:The incidence of proven bacterial infection in the ciprofloxacin-treated group was significantly lower than that of placebo group (10%vs 45%, p < 0.001). The incidences of bacteremia, spontaneous bacterial peritonitis, and urinary tract infection in the ciprofloxacin-treated group were significantly lower than those in the placebo group (0%vs 23%, 3.3%vs 13%, and 5%vs 18%, respectively; p < 0.05, respectively). Multivariate logistic regression analysis showed that a lack of prophylactic treatment with ciprofloxacin and severity of cirrhosis were the independent significant predictors for cirrhotic patients with acute gastrointestinal bleeding with infection.Conclusions:Prophylactic intestinal decontamination with oral ciprofloxacin is effective in the prevention of bacterial infections in patients with cirrhosis who were suffering from acute upper gastrointestinal hemorrhage.

Prognostic value of Plasma endotoxin levels in patients with cirrhosis

BACKGROUNDnEndotoxemia has frequently been observed in patients with cirrhosis. Previous studies have shown that cirrhotic patients with endotoxemia have a higher mortality than those without. We evaluated the clinical value of plasma endotoxin level in predicting short-term (3 months) and long-term (2 years) survival among cirrhotic patients and compared it with the Child-Pugh score.nnnMETHODSnPlasma endotoxin levels were determined in 102 cirrhotic patients without clinical evidence of infection by a quantitative Limulus assay. The patients were followed up for 3 months to assess short-term survival and for 2 years for long-term survival.nnnRESULTSnPlasma endotoxin levels increased progressively as liver function deteriorated. In short-term survival analysis, plasma endotoxin levels were significantly higher in non-survivors than those in survivors (10.6 +/- 2.2 pg/ml versus 5.8 +/- 0.5 pg/ml; P < 0.05). Both plasma endotoxin and serum bilirubin levels, but not the Child-Pugh score, were significant factors in predicting short-term survival in multivariate analysis. In long-term survival analysis, plasma endotoxin levels did not differ significantly between survivors and non-survivors (6.1 +/- 0.6 pg/ml versus 7.3 +/- 1.1 pg/ml; P > 0.05) and was not an independent predictor of long-term survival. In contrast, both Child-Pugh score and serum bilirubin levels were significant predictors of long-term survival in multivariate analysis.nnnCONCLUSIONSnIn patients with cirrhosis, plasma endotoxin levels progressively increase as liver function deteriorates and may be useful in predicting short-term survival.

A randomized controlled trial comparing octreotide and vasopressin in the control of acute esophageal variceal bleeding

This randomized controlled trial was conducted to compare the efficacy of intravenous infusion of octreotide (a synthetic long-acting somatostatin analogue) with vasopressin in 48 cirrhotic patients with endoscopically proven bleeding esophageal varices. Twenty-four patients received a continuous infusion of octreotide 25 micrograms/h for 24 h after an initial bolus of 100 micrograms and another 24 patients received a continuous infusion of vasopressin 0.4 U/min for 24 h. Bleeding was initially controlled after 6 h of drug infusion in 88% (21/24) and 54% (13/24) of the patients treated with octreotide and vasopressin respectively (p = 0.03). Complete control of bleeding after 24 h of drug infusion was achieved in 15 (63%) patients receiving octreotide and in 11 (46%) patients receiving vasopressin (p > 0.05). Side effects during drug infusion such as headache, chest pain and abdominal pain were significantly lower in the octreotide group (3/24) than in the vasopressin group (11/24). Serum gastrin and insulin levels fell significantly following octreotide infusion, but plasma glucose levels remained unchanged. Mortality related to bleeding esophageal varices was no different between the two groups. This report showed that octreotide infusion was more effective and had fewer side effects than vasopressin in initial controlling of acute esophageal variceal bleeding until an elective endoscopic sclerotherapy could be performed.

Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C.

Elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C is not uncommonly seen, but the pathogenesis of this phenomenon remains unclear. The aims of this study were to assess the prevalence of elevated serum AFP in patients with chronic hepatitis C and to evaluate the clinical, virologic, and histopathologic significance of this phenomenon. One hundred and fifteen Chinese patients with a histologic diagnosis of chronic hepatitis C were enrolled. None had evidence of hepatocellular carcinoma by image study at enrollment and for at least 2 years follow-up. Of the 115 patients, 33 (29%) had elevated serum AFP (more than 12 ng/mL). There was a significantly lower mean serum albumin (4.0 ± 0.1 vs. 4.3 ± 0.1 gm/dL, p <0.001) and higher mean scores for periportal necroinflammation (3.3 ± 0.3 vs. 2.3 ± 0.2, p = 0.007) and fibrosis (2.3 ± 0.2 vs. 1.1 ± 0.1, p < 0.001) in patients with elevated serum AFP when compared with patients without elevated serum AFP. Patients with elevated serum AFP had significantly more incidences of genotype 1b infection when compared with patients without elevated serum AFP (77% vs. 51%, p = 0.021). Mean serum hepatitis C virus (HCV) RNA titer showed no significant difference between the two groups. Multivariate logistic regression analysis showed that as serum albumin of less than 4.2 gm/dL, a histology fibrotic score of more than 3, and HCV genotype 1b infection were significantly independent predictors associated with elevated serum AFP. In conclusion, elevated serum AFP levels were significantly correlated with lower serum albumin levels, advanced fibrosis/cirrhosis, and genotype 1b infection in patients with chronic hepatitis C.

A randomized controlled trial of recombinant interferon α-2b in the treatment of Chinese patients with acute post-transfusion hepatitis C

To evaluate the efficacy of recombinant interferon alpha-2b in the treatment of patients with acute post-transfusion hepatitis C, a randomized controlled trial was conducted in 33 acute post-transfusion hepatitis C patients; 16 patients received 3 million units of subcutaneously injected recombinant interferon alpha-2b 3 times a week for 3 months and 17 patients without specific treatment were used as controls. At the end of the interferon treatment, 13 (81%) patients in the interferon-treated group normalized serum alanine aminotransferase compared with only six (35%) patients in the control group (p < 0.01). One year after completion of the interferon treatment, nine (56%) patients in the interferon-treated group and six (38%) patients in the control group normalized serum alanine aminotransferase (p = 0.35). Serum HCV-RNA measured by reverse transcription-polymerase chain reaction was positive in all patients at the time of enrollment and then became undetectable in 13 (81%) patients in the interferon-treated group and two (12%) patients in the control group at the end of interferon treatment (p < 0.001). One year after completion of the interferon treatment, seven (44%) patients in the interferon-treated group and two (13%) patients in the control group had persistent undetectable serum HCV-RNA (p = 0.08). Using a logistic regression model, the lower pretreatment level of serum HCV-RNA measured by quantitative branched DNA signal amplification assay was the only predictor for a favorable response to the interferon treatment in acute hepatitis C patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B.

In order to evaluate the incidence, predisposing factors and clinical course of antituberculous drug‐induced liver injury in hepatitis B surface antigen (HBsAg)‐positive carriers and non‐carriers, in an area endemic for hepatitis B, we prospectively followed 240 patients (154 male, 86 female; mean age 40 years) who had received daily isoniazid, rifampicin, ethambutol and pyrazinamide for the treatment of pulmonary tuberculosis. Patients with heavy alcohol consumption, with pretreatment serum alanine aminotransferase (ALT) elevation and who had less than 3 months post‐treatment follow‐up were excluded from the study. Thirty‐one (13%) patients were positive for serum HBsAg before treatment. Sixty‐three (26%; 95% CI: 21–32%) patients developed antituberculous drug‐induced liver injury. The incidence of drug‐induced liver injury was significantly more frequent in patients > 35 years of age than in patients > 35 years of age (33 vs 17%; P < 0.05), but was not different between HBsAg carriers and non‐carriers (29 vs 26%; P > 0.05). Using step‐wise logistic regression analysis, patient age > 35 years was the only independent variable for predicting antituberculous drug‐induced liver injury, while sex, acetylator phenotype, HBsAg carrier status and severity of tuberculosis were not. The peak serum ALT levels in antituberculous drug‐induced liver injury were not significantly different between HBsAg carriers and non‐carriers. Only one 61‐year‐old HBsAg carrier developed severe jaundice after 6 months antituberculous therapy; he subsequently died of hepatic failure. In conclusion, the incidence of antitubercuious drug‐induced liver injury was significantly higher in patients > 35 years of age than in patients > 35 years of age, but was not different between HBsAg carriers and non‐carriers. Mortality occurred in an aged HBsAg carrier superimposed with antituberculous drug‐induced liver injury.

Evaluation of hepatitis B and C viral markers : Clinical significance in Asian and Caucasian patients with hepatocellular carcinoma in the United States of America

Abstractu2002 In order to evaluate the roles of hepatitis B virus (HBV) and hepatitis C virus (HCV) and their clinical significance in Asian‐American and Caucasian patients with hepatocellular carcinoma (HCC) in the USA, 110 HCC patients, seen in a community‐based teaching hospital in the Los Angeles area over a 10 year period, were enrolled. Seventy‐nine (72%) patients were Asian‐Americans and 31 (28%) were Caucasians. Of the 110 HCC patients, 69 (63%) were positive for serum hepatitis B surface antigen (HBsAg), 26 (24%) were positive for serum antibody to hepatitis C virus (anti‐HCV), five (all Asian‐Americans) were positive for both markers; 11 (10%) patients had a history of alcoholism. HBsAg was detected in 63 (80%) Asian‐American patients, significantly higher than in the six (19%) Caucasian HCC patients (P < 0.01). Anti‐HCV was detected in 10 (32%) Caucasian and in 16 (20%) Asian‐American HCC patients (P > 0.05). Among Asian‐American HCC patients, anti‐HCV was more prevalent in those who were HBsAg‐negative than in the HBsAg‐positive patients (69 vs 8%; P < 0.01). A history of alcoholism was obtained in nine (29%) Caucasian HCC patients, significantly higher than in the two (3%) Asian‐American HCC patients (P < 0.05). Comparing HCC patients with positive HBsAg and with anti‐HCV, HBsAg‐positive HCC patients were younger, Asian‐Americans and predominantly male; 38% had a family history of liver disease. In contrast, anti‐HCV‐positive HCC patients were older by nearly a decade and 46% had a history of blood transfusion. Using a stepwise logistic regression analysis, Asian race and patient age < 50 years were found to be independent predictors for HBsAg‐positivity, while a history of blood transfusion was the only predictor for anti‐HCV‐positivity in HCC patients. There was no significant difference in the rate of cirrhosis, serum levels of alpha‐fetoprotein and survival between HBsAg‐positive and anti‐HCV‐positive HCC patients. In conclusion, chronic HBV infection was the major aetiological factor in Asian‐American HCC patients, while chronic HCV infection and alcoholism were major aetiological factors in Caucasian HCC patients in the USA.

Factors predictive of liver cirrhosis in patients with chronic hepatitis B: a multivariate analysis in a longitudinal study.

Objective and design Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis; however, factors associated with the development of cirrhosis have been incompletely studied. A total of 516 patients with chronic hepatitis B were followed up longitudinally to determine their outcome. Methods The clinical and pathological features were compared between those with and without cirrhosis occurrence. The risk factors were analysed, and the probability of the development of cirrhosis was estimated. Results During a mean follow‐up period of 5.7 ± 3.4 years (range 1‐17 years), cirrhosis occurred in 71 patients, with a calculated annual incidence of 2.4%. Older age (> 45 years) at entry, male gender, persistent hepatitis (> 1.5‐fold rise of serum alanine aminotransferase levels for at least one year) and diabetes mellitus were identified as independent risk factors of cirrhosis in a multivariate analysis (odds ratios 8.0, 19.3, 2.0 and 5.2, respectively; P values all < 0.05). A logistic regression equation was used to predict the probability of cirrhosis occurrence, which was as high as 76.6% when all risk factors were present. Acute exacerbation or super‐infection by hepatitis C or D viruses were not significant predictors. Patients with subsequent cirrhosis had higher initial hepatic histological necro‐inflammatory activities when compared to age‐ and sex‐matched non‐cirrhotic controls (Knodells scores: 8.2 ± 2.4 versus 6.0 ± 4.1, P < 0.05). Conclusions Patients who were elderly, male, diabetic or had a history of persistent and histologically severe hepatitis were at increased risks of liver cirrhosis. Aggressive anti‐viral therapy may be needed for these patients and they should be closely monitored for HBV‐related late complications. Eur J Gastroenterol Hepatol 12:687‐693