Minoru Ayada

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection

Background and Aim:  Evidence showing a higher prevalence of diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection has been accumulating. However, the reason why chronic HCV infection promotes DM remains unknown. In the present study, the authors focused on non‐cirrhotic and non‐diabetic patients with chronic HCV infection and evaluated the factors responsible for increases in insulin resistance.

Expression of Toll-like receptors in chronic hepatitis C virus infection

Background:  Toll‐like receptors (TLRs) are involved in innate immunity. Certain viruses interact with TLRs and mediate antiviral effects as well as immune responses. The aim of this study was to investigate the effect of TLRs on pathogenesis in hepatitis C virus (HCV)‐infected patients.

Identification of European-type hepatitis E virus subtype 3e isolates in Japanese wild boars: Molecular tracing of HEV from swine to wild boars

Nucleotide sequences of hepatitis E virus (HEV) isolates infecting wild boars in Mie prefecture, which is located in the central region of Japan and is far from the most prevalent regions of HEV infection in Japan, were determined and characterised. Among 144 serum samples of wild boars captured in Mie prefecture, 7 were positive for HEV-RNA. The nucleotide sequence of nearly the entire genome was determined for 4 of the 7 positive samples. Phylogenetic tree analyses indicated that 6 samples were subtype 3e and 1 was subtype 3a among the 7 isolates. We identified the indigenization of subtype 3e isolates in Japanese wild boars. Furthermore, 5 subtype 3e isolates were closely related and were located in the peripheral branch of subtype 3e isolates from European countries in the phylogenetic tree. The structure indicated that the ancestor of the 5 subtype 3e isolates originated in Europe. The phylogenetic structure and coalescent analyses suggested that the subtype 3e isolates entered Japan from Europe by importation of large-race pigs around 1966. The results also indicated that several lineages of subtype 3e expanded to a wide area of Japan around 1992 and 1 of the lineages was indigenized in wild boars in Mie prefecture between 1992 and 2009. The appearance of a wild boar cluster in the peripheral branch in the phylogenetic lineage may indicate the direction of gene flow of HEV subtype 3e from swine to wild boars. Clarification of the transmission direction or route should be helpful to prevent a future endemic or epidemic of HEV infection.

New findings regarding the epidemic history and population dynamics of Japan-indigenous genotype 3 hepatitis E virus inferred by molecular evolution.

Since previous studies have investigated the population dynamics of Japan‐indigenous genotype 3 hepatitis E virus (HEV) using virus sequences, more nucleotide sequences have been determined, and new techniques have been developed for such analysis.

Deficiency of forkhead box P3 and cytotoxic T-lymphocyte-associated antigen-4 gene expressions and impaired suppressor function of CD4(+)CD25(+) T cells in patients with autoimmune hepatitis.

Aim:  Recently, forkhead box P3 (Foxp3), cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4), glucocorticoid‐induced tumor necrosis factor receptor family‐related gene (GITR), and CD28 were identified as the key molecules that control the development and activation of CD4+CD25+ regulatory T cells (T‐reg). We investigated the expression pattern of these molecules on T‐reg, and investigated the ability of T‐reg to produce cytokines in patients with autoimmune hepatitis (AIH).

Molecular epidemiology and genetic history of European-type genotype 3 hepatitis E virus indigenized in the central region of Japan.

In Mie prefecture in Japan, 12 cases of sporadic hepatitis E occurred from 2004 to 2011. Mie prefecture is located in the central region of Japan, far from the most prevalent regions of hepatitis E virus (HEV) infection in Japan, the north and northeastern part. These 12 cases did not have any common risk factors of HEV infection. We analyzed the molecular epidemiology of the cases in Mie prefecture. We obtained the nucleotide sequences of the HEV strains and analyzed them with the sequences of other HEV strains by phylogenetic and coalescent analyses. Japan-indigenous genotype 3 HEV strains were divided into two major subtypes, namely, 3a and 3b; one minor subtype, 3e; and a few other unassigned lineages. The Japan-indigenous subtype 3e strains were closely related to European subtype 3e HEV strains and were comparatively rare in Japan; however, eight strains of the 12 cases we examined belonged to subtype 3e, indicating a close phylogenetic relationship, despite the lack of common risk factors. Coalescent analyses indicated that the Mie 3e strains seemed to have intruded into Mie prefecture about 10 years ago. Sporadic acute hepatitis E cases caused by the 3e strains occurred consistently from 2004 to 2011 in Mie prefecture. This is the first report of unexpected persistent occurrence of hepatitis by the European-type genotype 3 HEV, subtype 3e, in a country outside of Europe. Phylogenetic and coalescent analyses traced the history of the indigenization of the Mie 3e strains from Europe. Because hepatitis E cases caused by 3e strains are relatively rare in Japan, molecular evolutionary analyses of HEV infection in Mie prefecture is important for preventing a future hepatitis endemic or epidemic by 3e strains in Japan.

Investigating the origin and global dispersal history of hepatitis E virus genotype 4 using phylogeographical analysis.

Hepatitis E virus (HEV) genotype 4 has mainly been isolated from sporadic hepatitis cases and swine in Asian countries. We analysed the origin and global dispersal history of genotype 4 using a Bayesian phylogeographical approach.

Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction

Aim:  Human hepatocytes are known to express an array of inflammatory cytokines and chemokines. In this study, we examined the potential roles of hepatocytes in regulating immune responses in the liver, by assessing the induction of Th1‐ or Th2‐specific chemokines in HepG2 cells after various inflammatory stimulations.

Hepatocellular Carcinoma 11 and a Half Years after the Resolution of Chronic Hepatitis C Virus Infection Successfully Treated with Interferon

A 41-year-old Japanese man had received successful interferon (IFN) therapy against chronic hepatitis C in 1994. Since then, serum hepatitis C virus (HCV) RNA had been negative, and aminotransferase levels had been continuously normal. He had abstained from alcohol. However, his serum aminotransferase levels showed slight elevation as his body weight increased gradually. He was diagnosed as having fatty liver and diabetes mellitus. In January 2006, 11 and a half years after the resolution of HCV infection, he was found to have a hepatic nodule 4.0 cm in diameter at liver S4/8 region by plain abdominal CT at an annual follow-up examination. He was diagnosed as having hepatocellular carcinoma (HCC) by angiography. The tumor was curatively resected and its histological diagnosis was moderately differentiated HCC. Noncancerous lesion of the liver revealed fibrosis of stage F2 and mild inflammation of grade A1 with mild steatosis. This case suggests that all patients with chronic HCV infection should be followed as long as possible for the potential development of HCC even after clearance of the virus.