International Hepatology Communications最新文献

Circulating virion-antibody complex has been identified previously in association with chronic phase of HCV infection. In the present study, we investigated whether and to what extent GBV-C virions in the circulation of infected host are bound to IgG. To enable direct comparison between GBV-C and HCV, we used plasmas that were positive for both GBV-C and HCV RNAs. Diluted plasma was incubated with anti-human IgG, centrifuged, and divided into supernatant and pellet, and viral RNA titers were compared between the two fractions. In all nine samples examined, HCV RNA was detected in the pellet with higher titers than in the supernatant. By contrast, GBV-C RNA titers in the supernatant were higher than or equal to those in the pellet, except for only one case. Our results suggest that GBV-C virions are less associated with IgG than HCV virions are, and this may reflect the absence of hypervariable regions within envelope proteins of GBV-C.

Crigler-Najjar syndrome (types I and II) and Gilbert's syndrome are familial disorders associated with severe to mild unconjugated hyperbilirubinemia. In these conditions, the activity of bilirubin UDP-glucuronosyltransferase (UGT1^∗1), which is located in the hepatocyte endoplasmic reticulum, is defective, and severely and moderately decreased, respectively. UGT1^∗1 is derived from one of the UGT1 genes. It has a promoter containing a TATA box and consists of exon 1A (which is one of the individual first exons) and common exons 2–5. UGT1^∗1 mRNA is formed by differential splicing of these exons. In recent years, gene analysis of these syndromes has been carried out, and genetic abnormalities have been clarified. Homozygous nonsense mutations, mis-sense mutations, and other relevant mutations of exons 1A-5 have been reported in almost all of the patients with Crigler-Najjar syndrome type I, while mainly homozygous mis-sense mutations of exons 1A, 2, and 5 have been reported in type II patients. Almost all patients with this syndrome (types I and II) show autosomal recessive inheritance. On the other hand, some patients with Gilbert's syndrome show heterozygous mis-sense mutations in exons 1A, 4, and 5, while others show homozygous 2-base pair-insertion mutation (TA) into the TATA box in the promoter region [A(TA)₇TAA; normal: A(TA)₆TAA]. The pattern of inheritance can be autosomal recessive or autosomal dominant. It has also been clarified that enzyme activity is lowered to about 30% (rather than 50%) by heterozygous mutations of the coding region, because of the occurrence of dominant negative mutation based on subunit-structure of the enzyme.

We measured the levels of three antibodies against core (JCC-2), E1 (E1–5), and $\text{E2}\text{NS1}$ (E2-1) hepatitis C virus (HCV) before and after interferon (IFN) therapy in 22 patients with chronic hepatitis C and assessed the relationship between the changes in these antibody titers and the response to IFN. The titers of serum JCC-2 and E2-1 antibodies before the IFN therapy did not show any significant relationship with IFN efficacy. In contrast, the titer of E1–5 antibody was significantly lower in the complete responder (CR) group than in the non-responder (NR) group. The JCC-2 antibody titer of the CR group to IFN therapy showed a significant decrease immediately, at 6 months and 1 year after the completion of IFN administration. However, that of the NR group either did not change or rose again 6 months or 1 year after therapy following an immediate short-term decrease. Thus the E1–5 antibody titer before IFN therapy and the JCC-2 antibody titer during IFN therapy seems to be a good indicator of IFN efficacy. In contrast, the E2-1 antibody did not correlate with IFN efficacy.

^99mTc-galactosyl human serum albumin (GSA) is a new scintigraphy agent which binds specifically to asialoglycoprotein receptors on hepatocytes, and can be used to evaluate hepatic function. Indocyanine green (ICG) is hepatic blood flow-dependent, while antipyrine plasma clearance is independent of blood flow and thus antipyrine plasma clearance is an excellent parameter with which to assess liver function. In this study, we investigated the relationship between GSA examination and antipyrine plasma clearance to assess the usefulness of GSA in evaluating metabolic function of the liver. Studies were performed on 22 patients with liver diseases. Antipyrine plasma clearance measurement, ICG testing and biochemical analysis of blood were performed at the same time as GSA examination. GSA HH15 and antipyrine plasma clearance showed a good correlation (r = −0.702, P < 0.0005). On the other hand, ICGR15 showed a poor correlation with antipyrine plasma clearance (r = 0.449, P < 0.05). The results of this study suggest, that hepatic function determined using GSA is more closely related to the metabolic capacity of hepatocytes than to hepatic blood flow.

Although the three GGTP mRNAs differ in their 5′ untranslated sequences (Type I–III), all give rise to the same GGTP protein. In this study, we analysed the relative abundance of the three GGTP mRNA species in alcohol-fed rat livers. The results showed that in the alcohol-fed livers, expression of type III mRNA was stronger than that of type I, while in the control livers, expression of type III mRNA was weaker than that of type I. Relative optical density of type III GGTP mRNA, using β-actin mRNA as a standard, was significantly higher in the alcohol group. In conclusion, type III GGTP mRNA of the 5′ untranslated region is strongly expressed in alcoholic liver injury.

It is widely known that the hepatitis C virus (HCV) genotype 1b is generally resistant to interferon (IFN) therapy. Some reports have described various predictive factors regarding the responsiveness to IFN therapy. In this study, we evaluated predictive factors, the age of the patients, the level of HCV-RNA, the total dose of (IFN) and the level of serum alanine aminotransferase (s-ALT), potentially regarding the responsiveness to IFN therapy for patients with HCV genotype 1b. In addition, the hypervariable region 1 (HVR1) quasispecies in association with interferon inefficacy has been reported. We investigated the HVR1 using a polymerase chain reaction (PCR) — single strand conformation polymorphism (SSCP) analysis and thus attempted to determine whether or not an analysis of HVR1 quasispecies can possibly be used as a predictive factor for the responsiveness to IFN therapy. We studied 104 consecutive cases of chronic hepatitis C patients with HCV genotype 1b. Eighty-four patients from 104 could be assayed for the HVR1 quasispecies. Seventeen patients had complete responses (CR) to interferon therapy, 67 patients had non responses (NR). In addition, there was a significant difference between CR and NR groups regarding the level of HCV-RNA; in contrast, there was no differences for the age of the patients, the total dose of IFN and the HVR1 quasispecies. The above findings thus suggested that the level of HCV-RNA may be a predictive factor regarding the responsiveness to IFN therapy. However, the HVR1 quasispecies was not found to be a predictive factor.

We have previously reported that serum eosinophil cationic protein (ECP_ levels are increased in primary biliary cirrhosis (PBC). However, little is known about the role of eosinophils in the pathogenesis of this disease. In this study, liver biopsy specimens obtained from 27 PBC patients (stage I: 11 cases; stage II: 9 cases; stage III: 5 cases; stage IV: 2 cases) were stained with a monoclonal antibody (EG2) produced against ECP in an attempt to elucidate whether EG2-positive eosinophils are involved in the destruction of bile duct in PBC. Needle liver biopsy specimens obtained from 24 patients with chronic hepatitis C (CHC) were used as controls. In PBC, more than 10 EG2-positive cells were noted per portal tract in 6 cases, less than 10 EG2-positive cells in 10 cases and none in 11 cases. In CHC, more than 10 EG2-positive cells were detected per portal tract in only one case, less than 10 EG2-positive cells in 3 cases and none in 20 cases. According to the semi-morphometric statistical analysis, the hepatic infiltration rate of EG2-positive activated eosinophils into the portal tract was significantly higher in PBC than in CHC. Based on the stages of PBC, the infiltration rate of EG2-positive cells was significantly higher in stages I and II than in stages III and IV. A significant correlation was found between EG2-positive cell infiltration and small round cell infiltration. These findings suggest that EG2-positive, activated eosinophils may be involved in the early stages of PBC when the inflammatory changes are localized in the portal tract. It is tentatively speculated that activated eosinophils may play a role possibly as effector cells in the immunopathogenesis of PBC.

In order to understand the mechanism underlying in dyslipoproteinemia accompanied with liver diseases, levels in apolipoproteins A-I, C-III and E mRNA expressions in various human parenchymal liver diseases were assessed by Northen blot analysis. The mRNA expressions were significantly decreased in liver cirrhosis and acute hepatitis as compared with controls and were correlated with serum albumin levels. This finding indicates that liver biosynthesis of these apolipoproteins is suppressed in parenchymal human liver disease. This could be one of the mechanisms causing the dyslipoproteinemia in the liver diseases. This is the first study to show decreased apolipoprotein gene expression in human parenchymal liver diseases.

A case of drug-induced hepatitis with severe cholestasis caused by voglibose, a new agent for treating noninsulin-dependent diabetes mellitus, is described. The patient presented with icterus and pruritis. Voglibose was administered for 3 months before abnormal liver function was detected. The lymphocyte blast transformation test was positive for voglibose (stimulation index = 536%). One month after the onset of icterus, the patient also developed cholangitis due to methicillin-resistant Staphylococcus aureus, and the serum total bilirubin level increased to above 40 mg/dl. He was treated with plasma exchange, but eventually died. Voglibose is only absorbed slightly after oral administration, and there have been no reports of hepatitis due to this drug. This is the first fatal case of voglibose-induced hepatitis combined with methicillin-resistant Staphylococcus aureus cholangitis.

The lateral diffusion constants of lipids (D₁) and proteins (D_p) in the plasma membranes of hepatocytes were measured in liver smears of male Fischer 344 rats, by means of the fluorescence recovery after photobleaching (FRAP) method, after ethinyl-estradiol (EE) treatment of 1 or 5 days. The main finding was that EE treatment results in significant decreases in both the D₁- and the D_p-values. These observations are interpreted in terms of the role of membrane physicochemistry in functions of the hepatocytes.