Virological efficacy of combination therapy with corticosteroid and nucleoside analogue for severe acute exacerbation of chronic hepatitis B.

The short-term prognosis of patients with severe acute exacerbation of chronic hepatitis B (CHB) leading to acute liver failure is extremely poor. We have reported the efficacy of corticosteroid in combination with nucleoside analogue in the early stages, but virological efficacy has not been documented. Our aim was to elucidate the virological efficacy of this approach. Thirteen patients defined as severe acute exacerbation of CHB by our uniform criteria were prospectively examined for virological responses to treatment. Nucleoside analogue and sufficient dose of corticosteroids were introduced as soon as possible after the diagnosis of severe disease. Of the 13 patients, 7 (54%) survived, 5 (38%) died and 1 (8%) received liver transplantation. The decline of HBV DNA was significant between the first 2 weeks (P = 0.02) and 4 weeks (P < 0.01). Mean reduction in HBV DNA during the first 2 weeks was 1.7 ± 0.9 log copies per mL in overall patients, 2.1 ± 0.8 in survived patients and 1.2 ± 0.9 in dead/transplanted patients. The decline of HBV DNA was significant between the first 2 weeks (P = 0.03) and 4 weeks (P = 0.02) in survived patients, but not in dead/transplanted patients. Our study shows that corticosteroid treatment in combination with nucleotide analogue has sufficient virological effect against severe acute exacerbation of CHB, and a rapid decline of HBV DNA is conspicuous in survived patients.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up.

There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 ± 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 ± 3.95 and 5.49 ± 4.53 × 10(3) /µL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 ± 0.31 and 0.33 ± 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 ± 140.0 and 100.5 ± 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period.

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B.

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.

Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test.

Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG-IFN-alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non-SVR patients with greater accuracy.

Hepatitis A virus (HAV) proteinase 3C inhibits HAV IRES-dependent translation and cleaves the polypyrimidine tract-binding protein.

Hepatitis A virus (HAV) infection is still an important issue worldwide. A distinct set of viruses encode proteins that enhance viral cap-independent translation initiation driven by an internal ribosome entry site (IRES) and suppress cap-dependent host translation. Unlike cytolytic picornaviruses, replication of HAV does not cause host cell shut off, and it has been questioned whether HAV proteins interfere with its own and/or host translation. HAV proteins were coexpressed in Huh-7 cells with reporter genes whose translation was initiated by either cap-dependent or cap-independent mechanisms. Among the proteins tested, HAV proteinase 3C suppressed viral IRES-dependent translation. Furthermore, 3C cleaved the polypyrimidine tract-binding protein (PTB) whose interaction with the HAV IRES had been demonstrated previously. The combined results suggest that 3C-mediated cleavage of PTB might be involved in down-regulation of viral translation to give way to subsequent viral genome replication.

A transforming growth factor beta type II receptor gene mutation common in sporadic cecum cancer with microsatellite instability.

Mismatch repair genes are the responsible genes for hereditary non-polyposis colon cancer, and mutation of these genes causes replication error (RER). In several RER-positive colon cancer cell lines, mutations of repetitive sequences of transforming growth factor beta (TGF-beta) type II receptor (RII) gene have been reported. Since TGF-beta inhibits cell proliferation, loss of response to TGF-beta is an important tumor progression step. In this study, the relationship between RER status and mutation of the RII gene was analyzed in 112 cases of various types of sporadic gastrointestinal and hepatobiliary cancer (41 with gastric, 49 with colorectal, 5 with gallbladder, and 17 with hepatic cancers). RER was found in 17 cases (4 with gastric, 12 with colorectal, and 1 with gallbladder cancer), and 10 of those (3 with gastric and 7 with colorectal cancer) showed mutations of the RII gene. Of interest was that in all seven cases with colorectal cancer, tumors were located at the cecum. These data indicate that mutation of the RII gene, presumably caused by abnormality of repair gene, play an important role in carcinogenesis of sporadic gastrointestinal cancer, especially at the cecum.

The prevalence of TT virus infection in renal transplant recipients in Brazil.

BACKGROUND: Recently, TT virus (TTV) was discovered as a potential causative agent for non-A-E hepatitis. Little is known about the prevalence of TTV infection in renal transplant recipients. METHODS: One hundred and seventeen Brazilian renal transplant recipients and 100 normal subjects were examined to determine the prevalence of TTV infection. The TTV DNA in serum and its genotype were examined using polymerase chain reaction and restriction enzyme length polymorphism, respectively. RESULTS: TTV DNA was detected in 63/117 (53.8%) renal transplant recipients in contrast to its detection in 10/100 (10%) normal subjects (P<0.001). There was no statistical difference in the distribution of TTV genotypes between these groups. There was no significant difference in clinical backgrounds between TTV positive and negative patients. CONCLUSIONS: These results indicate a risk for TTV infection in renal transplant recipients in Brazil. They also indicate that TTV itself might not have a strong correlation with the pathogenicity of liver diseases.

Infection with delta agent in Japan.

It is estimated that approximately 70 to 80% of the world's HBsAg carriers live in Southeast Asia, but studies of delta infection in this area are still limited. We studied 323 HBsAg seropositive patients in Japan, and 4 (1.2%) of them were found to be positive for anti-delta antibody, with none positive for delta antigen. These four patients did not belong to the known high-risk groups for delta infection. One HBeAg positive female gave birth to a baby girl, and perinatal transmission of hepatitis B virus and delta was successfully blocked by a combination of hepatitis B immunoglobulin and vaccine. This study in the Tokyo-Chiba area showed delta infection, though low in frequency, among ordinary Japanese citizens. It has been reported that delta antigen is highly infectious to HBsAg carriers and that its infection will cause severe liver damage. Once introduced, it could become epidemic among non-drug users in a country where hepatitis B virus infection is endemic. At this moment, the only way of preventing such a disaster appears to be to reduce the number of chronic carriers by interruption of vertical transmission.

[Molecular mechanism of hepatocarcinogenesis].

Hepatocellular carcinoma (HCC) in Japan is closely associated with the chronic liver diseases of infection with the hepatitis B or C viruses. Analysis of HCC tissues frequently detects loss of heterozygosity at chromosomes 1p, 4, 6q, 8p, 10q, 13q, 16q, 17p, and many genomic and epigenomic abnormalities have been found in p53, beta-catenin, p16CDKI, DNA mismatch repair genes, and others. However, no specific abnormal genetic or epigenetic changes for HCC have been found so far. The development of HCC has been reported in mice transgenic for the hepatitis B virus X gene or the hepatitis C virus core gene, and these viral proteins might play essential roles in hepatocarcinogenesis. Chronic hepatitis and fibrosis due to persistent viral infection might also influence the genomic instability of hepatocytes, leading to accumulation of genomic changes.

[Long-term treatment for non-A, non-B chronic hepatitis--effects on hepatitis C virus (HCV)].

We have treated 16 patients with chronic non-A, non-B hepatitis with short term (7-13 weeks) and long term (1 year) interferon. Sustained effect (normalization) of treatment was noted in all by long term treatment, where 7 of 8 with short term treatment showed flare-ups of transaminase after the therapy. In addition, negative turn of anti-HCV antibody was noted in 2 of 5 patients with long term treatment, whereas such change was noted in none of 6 anti-HCV antibody positive patients treated with short term treatment. These data suggest that long term interferon therapy may change natural course of chronic non-A, non-B hepatitis caused by HCV.

[Significance of total dose of IFN in the treatment of chronic hepatitis C].

Two hundred thirteen patients with chronic hepatitis C were treated with IFN for 4 to 52 weeks and complete response, in which ALT levels sustained within the normal value after more than 6 months following IFN treatment, was achieved in only 10% of the patients treated with less than 300 MU of IFN, whereas it was 42% in those treated with more than 500 MU, hence the total amount of IFN is important in the treatment of chronic hepatitis C. The duration of the treatment (4 to 52 weeks) made little difference in the response when more than 500 MU of IFN were administered.

[Heterogeneity of delta virus RNA sequences in Japan].

Hepatitis delta virus RNA sequences were determined in isolates from two Japanese patients, M and S, by polymerase chain reaction and direct nucleotide sequencing and compared with three isolates from Italy, USA and Taiwan. The sequence obtained for hepatitis delta virus RNA from patient M was 92-96% identical to the sequences obtained for three other strains of hepatitis delta virus, whereas the sequence of hepatitis delta virus RNA obtained from patient S was approximately 80% identical to the other sequenced strains. This suggests that the delta agent in Japan has a heterogeneous origin and the delta virus RNA sequence from Japanese patient S is the most divergent delta virus isolate yet analyzed.