Masaki Takeo

Iron Overload Is Associated with Hepatic Oxidative Damage to DNA in Nonalcoholic Steatohepatitis

Several lines of evidence have suggested that oxidative stress plays an important role for the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, by using immunohistochemical staining of liver biopsy samples, we measured hepatic 7,8-dihydro-8-oxo-2′ deoxyguanosine (8-oxodG), a DNA base-modified product generated by hydroxyl radicals, of 38 NASH patients and compared with 24 simple steatosis and 10 healthy subjects. Relation of hepatic 8-oxodG with clinical, biochemical, and histologic variables and changes after iron reduction therapy (phlebotomy plus iron–restricted diet) were also examined. Hepatic 8-oxodG levels were significantly higher in NASH compared with simple steatosis (17.5 versus 2.0 8-oxodG–positive cells/105 μm2; P < 0.0001). 8-oxodG was significantly related to iron overload condition, glucose-insulin metabolic abnormality, and severities of hepatic steatosis in NASH patients. Logistic regression analysis also showed that hepatic iron deposit and insulin resistance were independent variables associated with elevated hepatic 8-oxodG. After the iron reduction therapy, hepatic 8-oxodG levels were significantly decreased (from 20.7 to 13.8 positive cells/105 μm2; P < 0.01) with concomitant reductions of serum transaminase levels in NASH patients. In conclusion, iron overload may play an important role in the pathogenesis of NASH by generating oxidative DNA damage and iron reduction therapy may reduce hepatocellular carcinoma incidence in patients with NASH. (Cancer Epidemiol Biomarkers Prev 2009;18(2):424–32)

Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion

BACKGROUND/AIMS The aim of this study is to determine the clinical relevance of hepatic producing iron regulatory hormone-hepcidin, on iron overload in patients with chronic hepatitis C (CHC). METHODS Serum hepcidin was measured in 73 CHC patients by surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), and compared to those of healthy controls and anemia of inflammation patients, and analyzed their relationship to hepatic hepcidin mRNA expression levels and clinical, hematological, and histological findings. The sequential changes of hepcidin were investigated in 27 CHC patients treated with a 48 week-course of pegylated-interferon (PEG-IFN) plus ribavirin therapy. RESULTS Serum hepcidin was positively correlated with hepatic hepcidin mRNA levels, serum ferritin and the degree of hepatic iron deposition in CHC. Serum hepcidin-to-ferritin ratios were significantly lower in HCV positive patients than in HCV negative controls in both hyper- and normal-ferritinemic conditions. This relative impairment of hepcidin production was fully reversible after successful HCV eradication by PEG-IFN plus ribavirin, concomitantly with the improvement of the iron overload condition. CONCLUSIONS The impairment of hepatic hepcidin production occurring with chronic HCV infection may enhance iron toxicity and lead to disease progression, and modulation or supplementation of hepcidin may be beneficial for these conditions in CHC.

Lactoferrin inhibits hepatitis C virus viremia in chronic hepatitis C patients with high viral loads and HCV genotype 1b

carcinoma have been reported during the past 16 yr. The time interval between fine-needle aspiration/biopsy and recurrence has varied from as early as 3 wk to as late as 4 yr. Needle diameter, number of passes, and the surrounding liver parenchyma are the factors influencing the rate of recurrence (2). The risk of needle tract recurrence of liver tumor should be regarded as significant, especially in patients with small hepatocellular carcinoma for whom long term survival is expected after surgical resection or orthotopic liver transplantation (3). Hence, the role of needle biopsy in confirming hepatocellular carcinoma needs critical evaluation. It should possibly be reserved for cases not amenable to surgical resection or where hepatocellular carcinoma cannot be diagnosed with noninvasive imaging modalities and -fetoprotein levels.

Upregulation of transferrin receptor 2 and ferroportin 1 mRNA in the liver of patients with chronic hepatitis C

Background:  Iron accumulation has been reported to be associated with progression of liver injury. The mechanism of iron accumulation in the liver is not known. In the present study, hepatic messenger RNA (mRNA) expression of transferrin receptor (TfR)1, TfR2, and ferroportin (FP)1 was measured in patients with chronic hepatitis (CH).

Value of the extracellular water ratio for assessment of cirrhotic patients with and without ascites

Aims:  Ascites, which often complicates liver cirrhosis, is reported to be a factor that worsens the outcome. The aims of this study were to quantify body water compartment changes in cirrhotic patients, with and without ascites, and to elucidate the value of body water analysis for predicting the development of ascites.

Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C

Aim:  This study was conducted to determine the clinical relevance of hepcidin, a recently identified key iron regulatory hormone, in patients with chronic hepatitis C virus (C‐HCV).

Patients achieving clearance of HCV with interferon therapy recover from decreased retinol-binding protein 4 levels.

Summary.  Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the blood in several insulin‐resistant states. We investigated the association between plasma RBP4 and histological and biochemical characteristics of chronic hepatitis C (CHC), as well as changes in RBP4 levels following interferon therapy. Eighty‐one patients with CHC infected with genotype 1 received treatment with peginterferon plus ribavirin. Histological data were available for 41 out of 81 patients before treatment, and the degree of fibrosis, inflammation and steatosis was assessed. Plasma levels of RBP4 were determined in serial samples (before, at the end of treatment, and at 6 months post‐treatment). RBP4 levels were lower in CHC patients than in control subjects (34.6 ± 12.3 μg/mL vs 46.2 ± 10.5 μg/mL; P ≤ 0.001). Higher RBP4 levels were linked to lower alanine aminotransferase (ALT) (P < 0.01), higher cholinesterase (P < 0.01), hyperlipidaemia (P < 0.01), hyperglycaemia (P < 0.05), and higher platelet (P < 0.01) count in CHC patients. Plasma RBP4 levels tended to decrease concomitantly with the grade of histological fibrosis, activity, and steatosis. RBP4 levels at baseline were not a predictor of the response to antiviral therapy in CHC patients. After peginterferon plus ribavirin therapy, only patients who had achieved clearance of hepatitis C virus had higher post‐treatment RBP4 levels. This study suggests that an association between RBP4 levels and abnormal metabolic features, and that liver function may determine RBP4 levels in CHC patents. This is further supported by the observation that RBP4 levels increased significantly after treatment only in sustained virological response (SVR) patients and reached levels comparable to those of healthy subjects.

Different hepatitis C virus dynamics of free-virions and immune-complexes after initiation of interferon-α in patients with chronic hepatitis C

BACKGROUND/AIMS To elucidate the mechanisms of action of interferon (IFN) against hepatitis C virus (HCV), we studied the serum HCV dynamics of free-virions (FV) and immune-complexes (IC) in patients treated with IFN. METHODS FV and IC were separated by immunoprecipitation using anti-human immunoglobulin and quantified serially using real-time detection-polymerase chain reaction. RESULTS Initially [1st phase (0-24 h)], the FV decreased more rapidly compared to IC [exponential decay slope (EDS)=1.78+/-0.42 vs. 0.99+/-0.31 log10/day, P<0.001; half-life=5.65+/-2.02 vs. 12.5+/-2.83 h, P<0.0001], but at the 2nd phase (1-14 days), half-life of FV was significantly longer than that of IC (101+/-117 vs. 14.2+/-1.08 h, P<0.005). Regarding response to IFN, the decline slope was not significantly different at the 1st phase, but at the 2nd phase, the FV-HCV RNA decreased more slowly in non-responders than in sustained responders to IFN (EDS=0.05+/-0.02 vs. 0.34+/-0.19 log10/day, P<0.005; half-life=186+/-112 vs. 15.3+/-1.85 h, P<0.005). CONCLUSIONS The presence of escape mutants from the neutralizing antibodies may be involved in resistance to IFN. Analyzes of FV- and IC-HCV dynamics are useful for predicting the IFN efficacy and understanding the mechanism of IFN action in chronic hepatitis patients.