Shinichiro Tada

Reactivation of hepatitis B in a patient with Crohn’s disease treated using infliximab

We encountered a case of reactivation of hepatitis B virus after administration of infliximab for Crohn’s disease. The use of infliximab was considered because the patient displayed abdominal symptoms and perianal lesions. Transaminases were normal, and hepatitis B virus (HBV) DNA was undetectable before treatment, so no antiviral treatment was used, and infliximab and low-dose 6-mercaptopurine were administered. This treatment was effective, but liver dysfunction and reactivation of HBV were observed after the fourth injection of infliximab. This is the first report of Crohn’s disease for which infliximab use was continued even after reactivation of HBV was observed. However, liver dysfunction was not improved by lamivudine. Antiviral treatment should be considered before administration of infliximab for patients with HBV.

Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis.

Background and Aim:  The molecular mechanisms underlying the involvement of the renin‐angiotensin system in hepatic fibrosis are unclear. Recently, it was reported that a Rho kinase inhibitor prevented fibrosis of various tissues and that the Rho/Rho kinase pathway was involved in the renin‐angiotensin system of vascular smooth muscle cells. In this study, the involvement of the Rho/Rho kinase pathway on angiotensin II signaling in liver fibrogenesis and generation of steatosis was investigated.

Novel scoring system as a useful model to predict the outcome of patients with acute liver failure: Application to indication criteria for liver transplantation.

Aim:  In Japan, the indication for liver transplantation in patients with acute liver failure (ALF) is currently determined according to the guideline published in 1996. However, its predictive accuracy has fallen in recent patients. Thus, we attempted to establish a new guideline.

DNMT1 and DNMT3b silencing sensitizes human hepatoma cells to TRAIL-mediated apoptosis via up-regulation of TRAIL-R2/DR5 and caspase-8.

DNA methylation plays a critical role in chromatin remodeling and gene expression. DNA methyltransferases (DNMTs) are hypothesized to mediate cellular DNA methylation status and gene expression during mammalian development and in malignant diseases. In this study, we examined the role of DNA methyltransferase 1 (DNMT1) and DNMT3b in cell proliferation and survival of hepatocellular carcinoma (HCC) cells. Gene silencing of both DNMT1 and DNMT3b by targeted siRNA knockdown reduces cell proliferation and sensitizes the cells to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐mediated cell death. The proapoptotic protein caspase‐8 demonstrated promoter hypermethylation in HCC cells and was up‐regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. In addition, death receptor TRAIL‐R2/DR5 (TRAIL receptor 2/death receptor 5) did not exhibit promoter hypermethylation in HCC cells but was also up‐regulated by knockdown of DNMT1 and DNMT3b both at mRNA and protein levels. Consistent with this observation, the combined transfection of DNMT1‐siRNA plus DNMT3b‐siRNA enhanced formation of the TRAIL‐death‐inducing signaling complex formation in HCC cells. In conclusion, our data suggest that DNA methylation of specific genomic regions maintained by DNMT1 and DNMT3b plays a critical role in survival of HCC cells, and a simultaneous knockdown of both DNMT1 and DNMT3b may be a novel anticancer strategy for the treatment of HCC. (Cancer Sci 2010)

Clinical usefulness of edaravone for acute liver injury

Background: Edaravone, a newly synthesized radical scavenger, has shown an excellent effect on treating stroke patients. The effect of edaravone on carbon tetrachloride (CCl4)‐induced acute liver injury was examined.

Treatment of hepatitis C virus with peg-interferon and ribavirin combination therapy significantly affects lipid metabolism.

Aim:  We investigated lipid metabolism in patients with chronic hepatitis C virus (HCV), serotype 1, undergoing combination therapy with PEG‐IFN α‐2b (PEG‐IFN) and ribavirin (RBV).

Value of computed tomography-derived estimated liver volume/standard liver volume ratio for predicting the prognosis of adult fulminant hepatic failure in Japan

Background and Aims:  The prognosis of fulminant hepatic failure (FHF) has been improved but is still unsatisfactory, and liver atrophy has been reported as a poor prognostic factor for this disease. The aim of this study was to assess the clinical value of the estimated liver volume (ELV) compared to the standard liver volume (SLV) in patients with FHF.

Role of Erythrocytes as a Reservoir for Ribavirin and Relationship with Adverse Reactions in the Early Phase of Interferon Combination Therapy for Chronic Hepatitis C Virus Infections

ABSTRACT We investigated the relationship between serum ribavirin concentrations and clearance, as well as therapeutic efficacy and adverse reactions, in 97 Japanese patients with chronic hepatitis C virus infections treated with a 6-month course of high-dose alpha2b interferon (6 million units/day) plus ribavirin (600 to 800 mg/day) combination therapy. This randomized trial showed that the saturation of ribavirin uptake after taking ribavirin capsules does not occur within a dose range of 600 to 800 mg/day, which is a standard dosage used clinically in Japan. Serum ribavirin concentrations and clearance did not correlate with sustained virological response rates. Fourteen patients discontinued therapy because of adverse reactions, and sustained virological response rates were significantly reduced by discontinuation of therapy, while dose reduction of ribavirin did not alter the therapeutic effects. Ribavirin concentrations after 1 week and ribavirin clearance were significantly correlated with discontinuation of ribavirin; however, a multiple-regression analysis revealed that only hemoglobin concentration, but not ribavirin clearance, was a significant factor for discontinuation of therapy (odds ratio, 0.514; 95% confidence interval, 0.311 to 0.85; P = 0.0095). It appears that peripheral erythrocytes may act as a reservoir for ribavirin and regulate serum ribavirin levels in the very early phase of treatment.

Susceptibility of experimental autoimmune hepatitis in transgenic mice overexpressing the c-H-ras gene

Results from a recent study of ours have demonstrated the significant role of the wild‐type ras gene in the development of hepatocellular carcinoma in rasH2 mice having prototype human c‐H‐ras genes. Chronic cell death and regeneration have been considered to work as co‐carcinogens with wild‐type ras gene overexpression in this model. To elucidate a role of gene overexpression in the occurrence of chronic inflammation, we tried to induce inflammation in the liver of rasH2 mice by immunizing them with the supernatant of a freshly prepared syngenic liver homogenate. Immunization resulted in a dense inflammatory infiltrate in the portal tract and focal necrosis with spots of fatty or foamy degeneration in the transgenic mouse liver; however, these observations were less frequently observed in non‐transgenic mouse liver. Monocytes, granulocytes and plasma cell infiltration were observed in the livers of transgenic mice. An immunohistochemical study showed that CD3‐positive lymphocytes also infiltrated the liver. The inflammatory infiltrate was still present in the transgenic liver 24 weeks after the last injection, but little infiltrate was observed at the same time in non‐transgenic mice. No hepatic tumours could be produced over the 6 months duration of the study and the results are only preliminary. However, these results do suggest that overexpression of wild‐type ras is partially responsible for the occurrence of autoimmune chronic hepatitis.

Interferon regulatory factor 1 promoter polymorphism and response to type 1 interferon.

The clinical success of interferon‐treatment has been found to vary in different individuals. To explain this, we hypothesized that responses to type 1 interferons could be partly determined by interferon regulatory factor‐1 gene transcription, because the latter is an important transcription factor in the interferon system. We demonstrated that the antiproliferative effect of type 1 interferons on human liver cancer cells correlates with levels of transcription of the interferon regulatory factor‐1 gene in parallel with those of p21WAF‐1 expression. Here, we investigated whether mutations in the interferon regulatory factor‐1 gene cause different responses to type 1 interferons. DNA from several human liver cancer cell lines and peripheral blood mononuclear cells was investigated. Nucleotide sequences of the interferon regulatory factor‐1 gene and polymerase chain reaction products of its upstream region were determined directly and after cloning. The promoter activity of the upstream region of this gene was measured by the luciferase reporter assay. We found 4 point mutations in the upstream (− 1 ∼ − 495) region, and the luciferase promoter assay demonstrated that these mutations did modify promoter activity. Analysis of DNA from healthy volunteers showed that these mutations are single nucleotide polymorphisms. These results suggest that single nucleotide polymorphisms of the interferon regulatory factor‐1 promoter contribute, at least in part, to determining responses to type 1 interferons. J. Cell. Biochem. Suppl. 36: 191–200, 2001.