Takashi Kosone

Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C.

To improve the efficacy of interferon (IFN) in the treatment of chronic hepatitis C, administration of IFN‐β twice per day was evaluated. Thirty‐eight patients with chronic hepatitis C (26 males and 12 females, aged 25–67 years) were included. Patients were treated with a new protocol that included twice‐daily treatment with IFN‐β. Three million units (MU) of IFN‐β was administered twice daily every day for 4 weeks followed by 10 MU of IFN‐α2b, every day for 2 weeks and then three times a week for 18 weeks (total IFN‐β, 148 MU; IFN‐α2b, 680 MU). Complete responders (CR) were defined by alanine aminotransferase levels that normalized within 6 months after completion of IFN therapy and remained normal for more than 6 months, and by serum hepatitis C virus (HCV) RNA levels that became negative as determined using the Amplicor® assay. Twenty‐one of 38 (55.3%) patients were CR. Nine of 21 (42.9%) patients with HCV serotype 1 were responders compared with nine of 12 (75.0%) patients with HCV serotype 2. In patients with an HCV titre greater than 1 million equivalents ml–1 (1 MEq ml–1), nine of 24 (37.5%) responded, and in patients with HCV titres less than 1 MEq ml–1, 12 of 14 (85.7%) responded. In patients with HCV serotype 1 and greater than 1 MEq ml–1 HCV RNA, four of 15 (26.7%) responded to IFN. Two‐thirds (66.7%) of the patients who became negative for HCV RNA after 2 weeks of therapy responded, while 72.7% of those with positive HCV RNA after 2 weeks of therapy were non‐responders. Proteinuria was frequently observed as an adverse effect of twice‐daily administration of IFN‐β. The combination of twice‐daily administration of IFN‐β for 4 weeks followed by IFN‐α showed a high response rate in patients with chronic hepatitis C, but in patients with both serotype 1 and a high titre of HCV RNA, response rates were still low. Thus, the HCV RNA titre 2 weeks after starting therapy with IFN was useful for predicting the eventual response to IFN.

Hepatocyte growth factor accelerates thrombopoiesis in transgenic mice

Hepatocyte growth factor (HGF) is one of the potent growth factors for liver regeneration and has a strong effect on epithelial and nonepithelial cells. As one of the pleiotropic functions, HGF acts as a hematopoietic regulator in the proliferation and differentiation of hematopoietic progenitors. However, the effect of HGF on the thrombopoietic function remains unclear. The correlation between HGF and thrombopoiesis was investigated in transgenic (TG) mice overexpressing murine HGF controlled by the murine HGF by the metallothionein promoter. Furthermore, the mechanism of thrombocytosis induced by HGF in vitro was analyzed in hepatoma cell line HepG2. Both the platelet count and the serum thrombopoietin (TPO) concentration were significantly higher in TG than in the wild type (WT) control mice. In the liver and spleen, the expression of TPOmRNA in TG was higher than that in WT by real-time polymerase chain reaction. The expressions of transcriptional factor of TPO, GABP-alpha/beta were more increased in TG liver compared to WT. In an in vitro study, HGF induced TPO and GABP-alpha/beta expression and enhanced TPO promoter activity. Therefore, HGF induced thrombopoiesis accompanied with the overexpression of TPO through GABP stimulation.

Gene expression profiles of drug-metabolizing enzymes and transporters with an overexpression of hepatocyte growth factor.

Background: It is important to elucidate the precise mechanism of drug metabolism during hepatic regeneration. Although cytochromes P450 (CYPs) are well known to be down‐regulated in growth‐stimulated cells, the overall gene expression profile of drug metabolizing enzymes are still not fully understood during hepatic regeneration. In this study, we investigated the gene expression profiles of such enzymes with an overexpression of hepatocyte growth factor (HGF).

Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury.

Background/Aims: Hepatocyte growth factor (HGF) inhibits liver fibrosis induced by carbon tetrachloride (CCl4) in animal models. NK2 is a natural splice variant of HGF, but its in vivo function remains to be elucidated. We investigated the in vivo effects of NK2 on CCl4‐induced liver fibrosis.

Integrative roles of transforming growth factor-α in the cytoprotection mechanisms of gastric mucosal injury

BackgroundTransforming growth factor α (TGFα) protects against gastric mucosal injury and facilitates wound healing. However, its overexpression is known to induce hypertrophic gastropathy resembling Menetriers disease in transgenic (TG) mice on an FVB background, as one of the authors reported previously. We studied another TGFα-expressing mouse line on a CD1 background, whose gastric mucosa appears normal. Since this TG mouse had a strong resistance to ethanol-induced gastric injury, we considered the long-term effect of TGFα on several gastric protection mechanisms.MethodsTGFα-expressing transgenic (TG) mouse lines bearing human TGFα cDNA under the control of the mouse metallothionein gene I promoter were generated on a CD1 mouse background, and analyzed their ethanol injury-resistant phenotypes produced by TGFα.ResultsIn the TG mucosa, blood flow was well maintained after ethanol injury. Further, neural and inducible types of NO synthases were consistently and widely expressed in the TG mucosa, compared with the limited distribution of neural type NO synthase in the luminal pit region of the wild-type (WT) mucosa. COX-2 and its upstream transcription factor NfkB were constitutively elevated in the TG mucosa even before ethanol administration, whereas they were induced in the same region of the WT mucosa only after ethanol injury. Two anti-apoptotic proteins, HSP70 and Bcl-2, were upregulated in the TG mucosa even before ethanol administration, while they were not expressed in the WT mucosa before the injury. Furthermore, pro-caspase 3 activation was inhibited in the TG mucosa, while it was converted to the active form in the WT mucosa following ethanol administration.ConclusionWe conclude that TGFα maintains the gastric mucosal defense against gastric injury by integrating other cytoprotective mechanisms.

Transforming growth factor‐α accelerates hepatocyte repopulation after hepatocyte transplantation

Background and Aim:  Although hepatocyte transplantation could be an alternative to orthotopic liver transplantation, many problems, such as rejection, location, required volume, and hepatocyte activity are currently unresolved. We previously demonstrated an anti‐apoptotic effect in transgenic mice overexpressing transforming growth factor (TGF)‐α. We herein present the details of a successful hepatocyte transplantation using TGF‐α transgenic mice.

Severe manifestation of acute hepatitis A recently found in Gunma, Japan.

Background:Background: The incidence of acute hepatitis A infection in Japan peaked 10 years ago and has been decreasing since then. However, an increase in severe cases of the disease has been documented recently. We experienced an outbreak in 1998–1999, and compared the clinical features of the disease in 1998–1999 (recent outbreak) and in 1987–1988 (past outbreak) in our prefecture (Gunma). Methods: Forty patients with acute hepatitis A were admitted to nine Gunma hospitals from October 1998 to September 1999. Their clinical features were compared with those of 100 patients with acute hepatitis A admitted to the same hospitals in 1987–1988. Results: Both outbreaks occurred mostly during the winter-spring season. Secondary familial infection was significantly decreased in the recent outbreak. Patients in the recent outbreak were 7 years older than those in the past outbreak. Laboratory findings, such as serum aspartatate aminotransferase (AST) and alanine aminotransferase (ALT) levels and prothrombin time, were worse in the recent than in the past outbreak. Severe-type hepatitis and fulminant hepatitis occurred in 5 patients (12.5%) in the recent outbreak but in only 2 patients (2.0%) in the past outbreak. Conclusions: Clinical data and manifestations were more severe in the recent outbreak than in the past outbreak of acute hepatitis A. It is important to be aware of hepatitis A virus infection and to take into account the available vaccination against hepatitis A virus in Japan.

The natural history of untreated hepatocellular carcinoma

AbstractBackground. Although early diagnosis and treatment of hepatocellular carcinoma (HCC) has become available through advances in diagnostic imaging and therapeutic modalities, there is still a need for recent data on the prognosis of untreated HCC. Therefore, we evaluated the natural history of patients with untreated HCC from various clinical viewpoints. Methods. Data from 70 untreated HCC patients (57 men, 13 women; aged 43–94 years) diagnosed from June 1992 to May 1997 at seven hospitals in Gunma Prefecture, Japan, were analyzed. Results. The overall mean survival was 5.3 ± 7.6 months from diagnosis to death. The median survival was 2.0 months from diagnosis to death; 12.0 months for tumor stage I, 6.8 months for tumor stage II, 8.6 months for tumor stage III, 2.0 months for tumor stage IV-A, and 2.0 months for tumor stage IV-B. According to clinical stage, the median length of survival of clinical stage I patients was 4.3 months; stage II, 4.3 months; and stage III, 1.4 months. In the 15 patients who refused any anti-cancer treatment, the median survival was 15.2 months and in the 55 patients who could not be given anti-cancer treatment because of poor liver function or advanced cancer the median survival was 1.6 months. The prognosis of patients with HCC complicated by portal thrombus was extremely poor. Multivariate analysis showed that portal thrombus and hypoalbuminemia were significant indicators of poor prognosis. Older patients with HCC had a poor prognosis, although the difference from prognosis in younger patients was not significant. Conclusions. Both tumor stage and clinical stage were correlated with duration of survival from diagnosis in these patients with HCC. The prognosis of untreated patients with HCC was extremely poor. All untreated patients died within 3 years of diagnosis.

Improvement of Proteinuria due to Combination Therapy with Daclatasvir and Asunaprevir in Hepatitis C Virus-associated Renal Disease without Cryoglobulinemia

We herein report a unique case of hepatitis C virus (HCV)-associated renal disease without cryoglobulinemia that showed proteinuria, hypoproteinemia, ascites, and edema. Due to combination therapy with daclatasvir and asunaprevir, the patient achieved sustained virological response at week 24 of the therapy. Furthermore, the therapy caused marked amelioration of her proteinuria, ascites, edema, and hypoalbuminemia, and finally improved her estimated glomerular filtration rate. There were no adverse events, and the combination therapy was well-tolerated. We recommend that HCV eradication with antiviral therapy using direct-acting antiviral agents be attempted first for all renal disease with HCV infection, regardless of cryoglobulinemia, considering the existence of resistance-associated variants.