Crucial role of impaired Kupffer cell phagocytosis on the decreased Sonazoid-enhanced echogenicity in a liver of a nonalchoholic steatohepatitis rat model.

AIMS: To evaluate the dynamics of Kupffer cell (KC) phagocytosis by performing both in vivo and in vitro studies using Sonazoid (GE Healthcare, Oslo) in a rat nonalcoholic steatohepatitis (NASH) model. METHODS: Contrast enhanced ultrasonography (CEUS) was performed on a rat NASH model induced by a methionine choline deficient diet (MCDD) and control rats, and Sonazoid was used to measure the signal intensity in the liver parenchyma. The uptake of Sonazoid by the KCs was observed by intravital microscopy. Their phagocytic capability was evaluated in vitro using isolated and cultured KCs. The uptake of fluorescein isothiocyanate (FITC)-labeled latex beads was observed and quantitatively analyzed by flow cytometry. RESULTS: In the MCDD group, liver parenchymal enhancement was reduced 20 min after the Sonazoid injection. Microscopic observation of the isolated and cultured KCs revealed that the number of phagocytosed Sonazoid microbubbles was significantly decreased. Confocal laser scanning microscopic (CLSM) observation showed a decrease in the uptake of the latex beads. A decreased phagocytic capacity in the MCDD group was suggested by the quantitative analysis using flow cytometry, as well as by intravital microscopy. CONCLUSIONS: CEUS with Sonazoid is a powerful evaluation tool to diagnose NASH from an early stage of the disease.

[A case of hepatocellular carcinoma with autoimmune hepatitis showing marked reduction of tumors by oral administration of UFT-E].

We report a case of hepatocellular carcinoma (HCC) in association with autoimmune hepatitis (AIH). In May 2003, a 66- year-old man was admitted to our hospital because of acute liver dysfunction. He was diagnosed with AIH, and his liver function was normalized by oral administration of the corticosteroid. In July 2007, when he was admitted for the treatment of bacterial pneumonia, two liver tumors (S4: ø4 cm and S2: ø1 cm) were revealed by abdominal CT scan, and the serum level of AFP was high. According to the findings of imaging diagnosis and laboratory data, the patient was diagnosed as having HCC. Since the standard invasive therapies of HCC were not accepted by the patient and his family, he was treated by oral administration of UFT-E (tegafur/uracil: 200 mg/day). Three months after the initiation of administration, CT scan showed a remarkable reduction of the tumors, and his serum AFP level was decreased to the normal range. This case shows that HCC develops in an AIH patient even if liver function is maintained in the normal range. It also suggests the clinical usefulness of UFT-E in the management of HCC given the difficulty of treatment by the standard therapies.

Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma.

PURPOSE: This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC). METHODS: This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks. RESULTS: There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045-0.561, P = 0.004), and the serum albumin level was retained. CONCLUSION: These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.

Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2).

BACKGROUND: Vitamin K(2) has been reported to suppress the growth of human hepatocellular carcinoma (HCC) in vitro and hepatocarcinogenesis in hepatitis C virus (HCV)-related cirrhosis in vivo. Hepatoma-derived growth factor (HDGF) is a unique nuclear targeting growth factor that is highly expressed in HCC cells and is a possible prognostic factor for patients with HCC. We investigated the regulation of HDGF expression by vitamin K(2). METHODS: Three HCC-derived cell lines, HepG2, HuH-7, and SK-Hep-1, were used. Cell number was determined with the MTT assay. The expression levels of HDGF mRNA and protein were measured by the real-time reverse transcriptase-polymerase chain reaction (PCR) method and ELISA and Western blot analysis, respectively. The HDGF promoter activity was measured by a dual luciferase-reporter assay. RESULTS: Vitamin K(2) suppressed the growth of the three HCC cell lines in a dose-dependent manner. Vitamin K(2) significantly suppressed the expression of the HDGF protein and mRNA in three cell lines. By a luciferase assay, vitamin K(2) significantly suppressed the promoter activity of the HDGF protein. Based on some luciferase-reporter plasmids containing truncated promoter regions, the possible responsive site of vitamin K(2) seems to reside in the region -1 to -150 bp of the HDGF gene. CONCLUSIONS: These findings suggested that regulation of the HDGF gene expression is one of the crucial mechanisms of vitamin K(2)-induced cell growth suppression for HCC.