Sohji Nishina

Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis

The liver is the major iron storage organ in the body, and therefore, iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation, even though its level should be recognized to be basically mild to moderate and sometimes within the normal range. The mechanisms underlying hepatic iron accumulation in chronic hepatitis C have not been fully elucidated. Reduction of the hepcidin transcription activity by hepatitis C virus (HCV)‐induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin‐bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV‐related chronic liver disease. However, even mild‐to‐moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C probably by reinforcing the HCV‐induced oxidative stress through Fenton reaction. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in this disease and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis.

Mitochondrial reactive oxygen species as a mystery voice in hepatitis C

There are several lines of evidence suggesting that oxidative stress is present in hepatitis C to a greater degree than in other inflammatory liver diseases and is closely related to disease progression. The main production site of reactive oxygen species (ROS) is assumed to be mitochondria, which concept is supported by evidence that hepatitis C virus (HCV) core protein is directly associated with them. The detoxification of ROS also is an important function of the cellular redox homeostasis system. These results draw our attention to how HCV‐induced mitochondrial ROS production is beyond redox regulation and affects the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis C. On the other hand, HCV‐related chronic liver diseases are characterized by metabolic alterations such as insulin resistance, hepatic steatosis and/or iron accumulation in the liver. These metabolic disorders also are relevant to the development of HCC in HCV‐related chronic liver diseases. Here, we review the mechanisms by which HCV increases mitochondrial ROS production and offer new insights as to how mitochondrial ROS are linked to metabolic disorders such as insulin resistance, hepatic steatosis and hepatic iron accumulation that are observed in HCV‐related chronic liver diseases.

A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice.

Background/Aim: A European randomized trial showed biochemical effects of 6‐month treatment with Stronger Neo‐Minophagen C™ (SNMC), a glycyrrhizin‐containing preparation, in patients with chronic hepatitis C, but its underlying mechanisms remain elusive. We reported previously that SNMC exhibits an anti‐oxidative effect in hepatitis C virus (HCV) transgenic mice that develop marked hepatic steatosis with mitochondrial injury under iron overloading. Hepatic steatosis and iron overload are oxidative stress‐associated pathophysiological features in chronic hepatitis C. The aim of this study was to investigate whether long‐term treatment with SNMC could prevent the development of hepatic steatosis in iron‐overloaded HCV transgenic mice.

Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice

Branched‐chain amino acids (BCAA) reduce the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the mechanisms that underlie these effects remain unknown. Previously, we reported that oxidative stress in male transgenic mice that expressed hepatitis C virus polyprotein (HCVTgM) caused hepatic iron accumulation by reducing hepcidin transcription, thereby leading to HCC development. This study investigated whether long‐term treatment with BCAA reduced hepatic iron accumulation and oxidative stress in iron‐overloaded HCVTgM and in patients with HCV‐related advanced fibrosis.

Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease

Little is known about the effects of non‐alcoholic fatty liver disease (NAFLD) on energy metabolism, although this disease is associated with metabolic syndrome. We measured non‐protein respiratory quotient (npRQ) using indirect calorimetry, which reflects glucose oxidation, and compared this value with histological disease severity in NAFLD patients.

Assessment of clinical and MRI features of de novo hypervascular HCC using gadoxetic acid-enhanced MRI.

To clarify the clinical and magnetic resonance imaging (MRI) features of de novo hypervascular hepatocellular carcinoma (HCC) using serial gadoxetic acid‐enhanced MRI.

Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate‐activated protein kinase/proliferator‐activated receptor gamma co‐activator 1 alpha signaling

Oxidative stress plays an important role in hepatocarcinogenesis of hepatitis C virus (HCV)‐related chronic liver diseases. Despite the evidence of an increased proportion of females among elderly patients with HCV‐related hepatocellular carcinoma (HCC), it remains unknown whether HCV augments hepatic oxidative stress in postmenopausal women. The aim of this study was to determine whether oxidative stress was augmented in ovariectomized (OVX) transgenic mice expressing the HCV polyprotein and to investigate its underlying mechanisms.

Key HLA‐DRB1‐DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine

Approximately 5‐10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome‐wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome‐wide SNP typing data. The GWAS identified independent associations of HLA‐DRB1‐DQB1, HLA‐DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA‐DRB1‐DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1‐DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1‐DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1‐DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA‐DR‐DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR‐DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).

Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10−4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A*33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: WFA+-M2BP predicts HCC in NAFLD

As it is not practical to perform regular screening for hepatocellular carcinoma (HCC) in all patients with non‐alcoholic fatty liver disease (NAFLD), there is a need to identify NAFLD patients who are at high risk for HCC. Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) has been shown to be a surrogate marker for predicting HCC as well as a liver fibrosis marker in patients with chronic hepatitis B and C. The aim of this study was to investigate whether WFA+‐M2BP predicts HCC development in NAFLD patients.