International Hepatology Communications最新文献

We studied the proliferative activity of hepatocellular carcinoma (HCC) by immunohistochemical staining with Ki-67, a monoclonal antibody to nuclear protein observed in the proliferative period of the cell cycle, and evaluated the usefulness of Ki-67 as a prognostic factor. Of the patients who underwent hepatectomy for HCC at our department, 56 cases in which pathological studies for the tumor showed no degeneration or necrosis were selected. Immunohistochemical staining was performed according to the method of Shi et al., using MIB-1 monoclonal antibody (Immunotech, SA) as a primary antibody. Ki-67 L.I. was significantly higher in chronic hepatitis (CH) and liver cirrhosis (LC) than in normal liver, and the L.I. was also significantly higher in non-cancerous tissue of the patients with HCC than in tissues with other liver diseases. In patients with a history of portal hypertension, the L.I. in non-cancerous liver tissue was significantly lower at the previous operation for portal hypertension without HCC than that at the subsequent operation for HCC. The L.I. was significantly higher in patients who showed a high serum AFP level and in those who had intrahepatic metastasis. It also tended to be higher in patients with vessel invasion, infiltration to capsule, aneuploidy tumor cells, and poor differentiation. The cumulative survival rate was significantly lower in patients with the L.I. of 10% or higher than in those with the L.I. of less than 10% in cancerous region. Recurrence was observed earlier after hepatectomy in patients with higher L.I. and the L.I. was significantly higher in those who had recurrence within 12 months. In the patients who could be followed up, the L.I. was significantly higher in those who had multiple recurrence after hepatectomy than in those who had single-lesion recurrence. The incidence of HCC was higher in patients with CH or LC in which the proliferative activity was abnormally enhanced for a prolonged period, suggesting that hepatocyte hyperproliferation triggers hepatic carcinogenesis. In addition, long-term survival was expected even in patients with advanced HCC if the L.I. in preoperative biopsy specimens was low, while in patients with high L.I., postoperative recurrence and distant metastasis may occur more frequently, and postoperative supplementary therapies may be necessary, even when the tumor is completely resectable. In conclusion, Ki-67 staining is considered to be useful for evaluation of the malignant potential of HCC.

It is yet not fully uncovered where and how translation starts in GB virus C or hepatitis G virus ($\text{GBV-}\text{C}\text{HGV}$), and, accordingly, information on structural proteins of this virus has been scarce. To know a vertebral architecture of $\text{GBV-}\text{C}\text{HGV}$ genome at least for its 5′ portion, we analyzed 31 Japanese isolates of $\text{GBV-}\text{C}\text{HGV}$. Our results indicated that most of the Japanese isolates were classifiable into ‘Japanese type’, two isolates into ‘North American type’, one into ‘African type’, and another into the fourth distinct type. Despite such sequence diversity across individual types, however, several common characteristics existed. (1) The AUG that resides just downstream of an oligopyrimidine tract was conserved by all isolates as the first in-frame initiation codon for the polyprotein. (2) The sequence upstream of this AUG had many covariant nucleotide substitutions, suggesting conserved secondary structure. (3) The ORF that starts with this AUG did not code for core. (4) Predicted amino acid sequence of putative E1 and E2 was highly conserved among different types, and did not contain hypervariable regions.

Background: To assess the effectiveness and side effects of interferon (IFN)γ therapy for chronic hepatitis C. Materials and methods: A single dose of 1 × 10⁶ IU of natural IFNγ was administered intramuscularly daily for 4 weeks to five patients with chronic active hepatitis C. Alanine aminotransferase levels, 2′-5′ oligoadenylate synthetase activity, β₂ microglobulin levels, IFNγ activity and HCV RNA levels were measured in sera. Results: ALT level, 2′-5′ oligoadenylate synthetase (2-5AS) activity, β₂ microglobulin (BMG) level, and IFNγ activity increased from 1–2 weeks after the start of IFNγ. However, HCV RNA levels did not decrease during IFNγ administration. There were no serious adverse reactions. Conclusions: IFNγ, which has attracted attention for its immunoenhancement, is worthy to be investigated as a therapy for chronic hepatitis C. However, the use of IFNγ in combination with IFNα, β or other antiviral agents may be more rewarding because of the possibly weak antiviral action of IFNγ.

Using newly-designed primers for semi-nested reverse transcriptase-polymerase chain reaction to detect 5′-untranslated region of $\text{HGV}\text{GB-C}$ hepatitis virus RNA, we screened 45 patients and found three $\text{HGV}\text{GB-C}$ positive patients (with fulminant hepatitis and liver cirrhosis, and on hemodialysis). Restriction fragment length polymorphism and single-strand conformation polymorphism analysis revealed a similar pattern in all positive specimens. The sequence amplified by our primers might be a highly conserved sequence. We believe our primers are useful for screening of $\text{HGV}\text{GB-C}$ virus RNA.

The effects of glycyrrihizin on liver-function, amounts of HCV RNA and viral complexity in patients with chronic hepatitis C were examined. The subjects were 27 type C chronic hepatitis patients who did not respond to previous interferon therapy. They were given 60 ml of Stronger Neo-Minophagen C, a preparation of glycyrrhizin combined with glycine and cysteine, three times a week for 16 weeks. The treatment was effective in 20 patients (74.1%), whose serum levels of aminotransferase fell to one half of that before treatment, but was not effective in seven patients (25.9%). No significant differences were noted at the beginning of the therapy in the backgrounds (age, sex, serum levels of aminotransferase, etc.( of the effective and non-effective groups. Also, no significant differences in HCV RNA quantity and viral complexity of HCV RNA were observed between the two groups. The results suggest that glycyrrhizin improves serum ALT levels without changing the amounts of HCV RNA and viral complexity, suggesting that the effect might depend on host factors such as the immune response.

Hepatitis G virus (HGV) RNA was measured in sera from 60 patients satisfying the international diagnostic criteria of definite autoimmune hepatitis type 1 using a reverse transcription and polymerase chain reaction with primers of the putative NS5 region of the HGV genome. Five patients had a history of blood transfusion. Of the 60 patients, 55 (92%) were confirmed as having human leukocyte antigen (HLA) DR4 or DR2 which are genetic markers for susceptibility to autoimmune hepatitis in Japanese. None of the 60 patients had any serum markers suggesting hepatitis B virus infection and 5 (8%) had evidence of on-going hepatitis C virus infection. No patients had HGV RNA in serum. The absence of active HGV infection in this cohort suggests that HGV does not play a casual role in the development of autoimmune hepatitis in Japan.

Gilbert's syndrome is a constitutional mild unconjugated hyperbilirubinemia. In patients with this syndrome, mutation in the promoter and coding region of UDP-glucuronosyltransferase 1^∗1 gene have been reported independently. In the present study, we examined mutations in UGT1^∗1 gene using leukocytes of one male and four female patients with Gilbert's syndrome. In two cases, heterozygous mis-sense mutation of Gly71Arg was detected in exon 1A with simultaneous heterozygous mutation in the promoter region (2-base pair (TA)-insertion in the TATA box; A(TA)₇TAA, normal: A(TA)₆TAA). In the other three cases, mutation was not detected in the coding region and the homozygous A(TA)₇TAA mutation was observed. From these results, it is concluded that either homozygous mutation (inherited recessively) in TATA box of the promoter region or heterozygous mis-sense mutation (inherited dominantly) in the coding region were present in the patients with Gilbert's syndrome.

Although a new RNA virus, designated hepatitis G virus (HGV) has recently been identified, the clinical significance of HGV infection is still unclear. To approach this problem, we studied the prevalence of HGV infection on patients with liver diseases in Japan by nested reverse transcription polymerase chain reaction using primers deduced from 5′-noncoding region. The positive rate of HGV RNA was 6.8% in all tested liver disease patients (45 of 663), while 1.4% ($\text{2}\text{145}$) in healthy individuals. Among these patients, HGV RNA was detected in 6.9% ($\text{4}\text{58}$) of acute hepatitis, 7% ($\text{16}\text{229}$) of chronic hepatitis, 8.6% ($\text{5}\text{58}$) of liver cirrhosis and 12.2% ($\text{17}\text{139}$) of hepatocellular carcinoma (HCC), but few or none in non-viral liver diseases. HGV coinfection with hepatitis B virus and hepatitis C virus (HCV) were present in 8.9 and 66.7% of these patients, respectively, while 22.2% of patients were positive for HGV alone. In 54 patients with acute hepatitis that is seronegative for hepatitis A-E, four of them (7.4%) were positive for HGV. Liver histology from a HCC patient infected with HGV alone revealed that lymphocytic infiltration of portal trcts in (69%) had not received blood transfusion. Nucleotide sequence analyses in four patients confirmed that these PCR products were derived from HGV genome sequences and 90% identical to those of HGV prototype from American patients, and 97% identical among Japanese isolates. These results indicate that generally 6.8% of Japanese patients with liver diseases had HGV infection and most of them was coinfected with HCV. This suggest that HGV might be related to liver diseases. The routes of transmission of HGV require clarification.

The early vascular injury in the liver was characterized in an experimental model of multiple organ failure (MOF). Significant increases of hyaluronic acid levels (660%) and plasma alanine aminotransferase activities (1050%) were observed after 20 min hepatic ischemia followed by 4 h reperfusion and injection of 0.5 mg/kg Salmonella enteritidis endotoxin at 30 min reperfusion. Morphological evaluation of sinusoids with transmission electron microscopy indicated neutrophil and Kupffer cell activation as well as damage or loss of sinusoidal endothelial cells. Hepatocellular injury was evident from fused microvilli and blebbed plasma membranes. Treatment with the 21-aminosteroid tirilazad mesylate (U-74006F) (2 × 3 mg/kg) reduced plasma hyaluronic acid levels by 61% and plasma transaminase activities by 69% suggesting a beneficial effect on sinusoidal endothelial cell and parenchymal cell injury. This was confirmed by morphology. Our data provide morphological and functional evidence for severe injury to sinusoidal endothelium and the vascular pole of hepatocytes in this model of MOF. U-74006F significantly protected the liver against this Kupffer cell- and neutrophil-mediated injury. Thus, U-74006F may be a promising therapeutic for liver dysfunction and failure during a local or systemic inflammatory response.