Difference of HBV genotype distribution between acute hepatitis and chronic hepatitis in Japan.

BACKGROUND: Recently genotype A which is rare in the patients in chronic hepatitis B (CHB) was frequently noted in patients with acute hepatitis B (AHB). To investigate their clinical and virological features, we studied the AHB patients in the past 5 years. PATIENTS AND METHODS: 98 patients with AHB and 80 patients with CHB admitted to our hospital between 1998 and 2003 were studied. RESULTS: Genotype A was not found in CHB but was frequently noted in AHB (p < 0.001). Comparison of the clinical features of acute hepatitis between the two major genotypes, A and C, homosexual and heterosexual with multiple partners were frequently seen among genotype A patients (p < 0.001). On the other hand, infection from steady partner showed a tendency to be more frequent in genotype C (p = 0.065). In genotype A, the levels of HBVDNA on admission was higher (p = 0.007) and AHB has significantly more frequently progress to chronic infection than in genotype C (p = 0.028). Phylogenetic analysis of genotype A revealed that almost all strains from homosexual men belonged not to the African type A1 but to the Western type A2. CONCLUSION: Genotype A has increased recently among AHB in Japan. This fact may correlate to promiscuous intercourse in high risk group. Prophylactic efforts should be considered to prevent the prevailing of genotype A.

TT virus genotype changes frequently in multiply transfused patients with hemophilia but rarely in patients with chronic hepatitis C and in healthy subjects.

BACKGROUND: TT virus (TTV), a novel DNA virus, was originally thought to be transmitted by transfusion. However, nonparenteral transmission is recently suspected to be a major mode of transmission. To investigate the possibility of reinfection with TTV in multiply transfused patients and to evaluate the significance of transfusion transmission of TTV in patients with hemophilia, serial changes in TTV genotype were investigated in three groups. STUDY DESIGN AND METHODS: Serial changes in TTV genotype were investigated in 16 multiply transfused patients with hemophilia, 16 age-matched patients with chronic hepatitis C, and 16 age-matched healthy subjects. RESULTS: Mixed infection with multiple TTV genotypes was common in all groups. However, changes in TTV genotype were frequent in patients with hemophilia (15/16; 93.8%) but rare in patients with chronic hepatitis C and in healthy subjects (each group: 1/16; 6.3%). CONCLUSION: Changes in TTV genotype were frequently observed in multiply transfused patients with hemophilia but not in patients with chronic hepatitis or in healthy subjects without risk of transfusion transmission. This difference may suggest that exposure to TTV or even reinfection occurs frequently in patients with hemophilia, which could be evidence of transfusion transmission of TTV in this population.

Cloning and sequencing of a novel human gene that encodes a putative target protein of Nesh-SH3.

By using a conventional two-hybrid technique with an Src homology 3 (SH3) domain of Nesh as the bait protein, a novel full-length cDNA was isolated and sequenced from a human placenta cDNA library. This cDNA consists of 3023 bp and has a predicted open reading frame that encodes 486 amino acids. It possesses an SH3 binding motif, a nuclear targeting sequence, and no catalytic domain. Overall, it has no similarity to known molecules involved in a signaling cascade. Polymerase Chair reaction-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels localized the gene on human chromosome 3q12 near the marker D3S1271.

Safety and complications of interventional radiology for hepatocellular carcinoma in patients with haemophilia and cirrhosis.

Many patients with haemophilia have been chronically infected with hepatitis virus owing to multiple transfusions and the prevalence of hepatocellular carcinoma will probably increase in this population. We evaluated the safety and complications of radiological intervention for hepatocellular carcinoma in eight patients with haemophilia and cirrhosis. Radiological interventions can be performed safely in all patients with haemophilia. Unexpectedly, the most common complication was bleeding from the gastrointestinal tract. Attention should be paid to this potential problem in order to take appropriate steps to minimize its occurrence.

Infection of hepatitis A virus in Japanese haemophiliacs.

OBJECTIVES: Outbreaks of hepatitis A virus (HAV) infection in haemophiliacs have been reported from many countries. The aim of this study was to determine the prevalence of hepatitis A virus antibody (HAVAb) in Japanese haemophiliacs. METHODS: Sixty-seven male haemophiliacs were recruited for this study of HAV infection. We also compared the rate of HAV infection with that of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis G virus (HGV). RESULTS: Fifteen of 67 haemophiliacs (22.4%) were positive for HAVAb. Prevalence of HAVAb was significantly higher in haemophiliacs than in Japanese normal subjects previously reported (P= 0.0001). Age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and prevalence of HIV, HCV, and HGV were not statistically different between HAVAb positive and HAVAb negative haemophiliacs. We suggest that the use of clotting factor concentrates is closely associated with HAV infection, but HAV infection does not have an effect on clinical course. CONCLUSIONS: Administration of clotting factor concentrates may increase risk of HAV infection in haemophiliacs.

Fatal bleeding from a residual vein at the esophageal ulcer base after successful endoscopic variceal ligation.

Endoscopic variceal band ligation (EVL) is now one of the accepted treatment options for esophageal varices, and the safety of this procedure has been proved. However, we experienced a patient who had a fatal massive bleeding after successful EVL for ruptured esophageal varix. Postmortem study revealed a residual vein at the base of the esophageal ulceration associated with the ligation, which was believed to be the site of the fatal bleeding. His platelet counts and prothrombin time were not very impaired. Our case indicates that fatal massive bleeding can occur in patients after successful EVL without specific risk factors and indicates the importance of the awareness of the possibility of these complications.

Effects of HAART on hepatitis C, hepatitis G, and TT virus in multiply coinfected HIV-positive patients with haemophilia.

In multiply coinfected human immunodeficiency virus (HIV)-positive patients, we investigated the effects of high-activity antiretroviral therapy (HAART) using HIV protease inhibitors on three other viruses: hepatitis C virus (HCV), hepatitis G virus (HGV), and TT virus (TTV). Viral concentrations were measured serially by polymerase chain reaction methods in five patients with quadruple infection (HIV, HCV, HGV, and TTV) and in two patients with triple infection (HIV, HCV, and HGV) before and during HAART. In addition, CD4+ cell counts and serum alanine aminotransferase (ALT) levels were measured serially. Generally we observed no difference in serum HCV RNA, HGV RNA, or TTV DNA concentrations between samples obtained before and after initiation of HAART, whereas HIV RNA concentration decreased and CD4 counts increased in most patients. However, two patients had markedly decreased concentrations of HCV RNA and HGV RNA, respectively, more than 12 months after beginning HAART. Normalization of serum ALT levels was observed in a patient with decline of HCV RNA concentrations. No interactions were observed among these four viruses. HAART had no apparent direct effects on HCV, HGV, or TTV. Further studies will be required to elucidate whether the restoration of immune status through suppression of HIV replication by HAART may affect HCV or HGV RNA concentrations.

Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy.

Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or both is common in hemophiliac patients due to putative transmission through clotting factor concentrates. Recently, highly active antiretroviral therapy (HAART) has been found to markedly improve viremia and immunologic parameters in patients infected with HIV. This report considers interactions between these viral infections, the immune system, and antiretroviral therapy. A total of 130 male hemophiliac patients were grouped according to type of viremia (HCV, HIV, both, or neither). Along with 30 healthy men age-matched to viremic patients, these groups were compared with respect to viral load and immunologic parameters. Thirty-five patients treated as above for HIV were serially followed up. HCV infection was associated with reduced peripheral B-cell and CD4(+)-cell counts and with increased serum IgG and IgM levels, whereas HIV infection was associated with reduced peripheral CD4(+)-cell counts and increased serum IgG and IgA levels. In patients with both viruses, HCV and HIV RNA load correlated inversely with peripheral B-cell and CD4(+)-cell counts, respectively. HAART reduced levels of both viruses in the blood. Of the 25 patients with both viruses, HAART eliminated HCV in 2. In conclusion, immunologic dynamics differed between hemophiliac patients infected with HCV, HIV, or both. The relative dynamics of HCV viral load, peripheral B-cell count, and serum IgM level were similar to those of HIV viral load, CD4(+)-cell count, and serum IgA. (Blood. 2000;96:4293-4299)

An autopsy case of multilocular cystic hepatocellular carcinoma without liver cirrhosis.

Although simple cysts, cystadenoma and cystadenocarcinoma of the liver have been well documented as hepatic cystic diseases, cystic hepatocellular carcinoma is a curious entity. Only 3 cases have been reported in the English literature. A 70-year-old man was admitted to Nagoya University Hospital for multiple liver tumors and a thrombus in the main trunk of the portal vein. A part of the tumors contained cystic components, and were diagnosed as hepatocellular carcinoma by needle biopsy. After giving informed consent, the patient was treated with several systemic chemotherapy using doxorubicin, fluorouracil, cyclophosphamide, cisplatin and oral anticancer agent UFT, a combination of uracil and tegafur, for almost 2 years. During this time, the tumors enlarged gradually, and also underwent cyst formation, the patients then died of biliary sepsis. Autopsy confirmed the diagnosis of multilocular cystic hepatocellular carcinoma without liver cirrhosis.

A case of the development of two hepatocellular carcinomas and a cholangiocarcinoma with cirrhosis after elimination of serum hepatitis C virus RNA with interferon therapy.

A 64-year-old man who had exhibited abnormal transaminase levels for about 20 years was admitted to a hospital for the treatment of liver damage. Laboratory testing demonstrated that he was suffering from chronic hepatitis C, and a liver biopsy showed chronic active hepatitis with septal fibrosis. He was treated with interferon-alpha, and HCV-RNA became undetectable. Four years after the completion of interferon treatment, 3 lesions in the patient's liver were revealed by routine ultrasonography, and he was referred to Nagoya University Hospital for further examinations on November 1997. Radiographical examinations such as computed tomography and angiography demonstrated 2 hypervascular tumors (size: phi 35 mm and phi 20 mm) and 1 hypovascular tumor (phi 28 mm). Qualitative analysis for HCV-RNA by polymerase chain reaction method was negative. Partial hepatectomy was performed, and pathological examination of the tumors showed 2 moderately differentiated hepatocellular carcinomas and cholangiocarcinoma accompanied with liver cirrhosis. We propose that even patients with disappearance of HCV-RNA after interferon therapy, especially with liver cirrhosis or severe fibrosis, should be followed-up closely and examined at regular intervals because of the high risk of developing primary liver cancers.

Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus-infected haemophiliacs.

We performed a pilot study to evaluate the factors associated with response to interferon (IFN) therapy for chronic hepatitis C (CHC) with human immunodeficiency virus (HIV) coinfected haemophiliacs. Seven haemophiliacs, coinfected with HIV and hepatitis C virus (HCV), received 9 mega-units (MU) of natural IFN-alpha daily during the first 2 weeks and then three times a week for 22 weeks, all injected subcutaneously. Six patients were receiving zidovudine (AZT) 600 mg day-1 and didanosine (ddI) 200 mg day(-1) during IFN therapy. This treatment was safe and well tolerated. Four patients had no detectable serum HCV-RNA at the end of therapy, but long-term, none of the seven patients achieved a sustained response, i.e. undetectable serum HCV-RNA with persistently normal serum alanine aminotransferase (ALT) 6 months after therapy. IFN did not affect CD4-positive cell counts. Most of our patients had high HCV-RNA loads and/or low CD4 counts, both unfavourable markers for IFN therapy. In conclusion, IFN therapy did not eradicate HCV from haemophiliacs coinfected with HIV.

Massive bleeding from a gastric erosion after transcatheter arterial chemoembolization for hepatocellular carcinoma in a patient with mild haemophilia A.

We observed massive bleeding from a gastric erosion following transcatheter arterial chemoembolization (TAE) in a patient with mild haemophilia A. A 78-year-old haemophiliac (factor VIII level over 60%) received TAE with farmorubicin and spongel. Haematemesis and melena with loss of consciousness occurred 3 days [corrected] after TAE, and endoscopy revealed superficial erosions with oozing. Toxic effects of the anticancer drug in conjunction with the bleeding disorder may have caused the massive bleeding. We should always consider the possibility of unexpected complications in patients with bleeding disorders; gastrointestinal bleeding can develop during treatment for liver tumours.

Investigation of the association between infection with Helicobacter pylori and with TT virus, a novel DNA virus, in patients with gastroduodenal ulcer or ulcer scar.

OBJECTIVE: Recently, a novel DNA virus (TT virus; TTV) has been isolated. Enteric transmission is suggested as a route of transmission of TTV, with high prevalence of this virus infection in the general population, and age and geographical distributions of TTV prevalence very similar to those of Helicobacterpylori infection. We analysed an association between TTV and H. pylori infection in patients with gastroduodenal ulcer or ulcer scar. METHODS: In 181 patients with a gastroduodenal ulcer or ulcer scar (102 with a gastric lesion, 60 with a duodenal lesion, and 19 with both sites involved), specimens were cultured for H. pylori and TTV infection was sought in serum by a polymerase chain reaction. RESULTS: H. pylori infection was demonstrated in 152 patients (84.0%) and TTV was detected in 168 patients (92.8%). Patients with TTV were significantly older than those without TTV (P = 0.0001), while no age difference was observed between patients with and without H. pylori infection. No difference was apparent in the prevalence of TTV infection between patients with and without H. pylori infection, and vice versa. CONCLUSIONS: We found no association between TTV infection and H. pylori infection in patients with peptic ulcer diseases, which is consistent with a lack of association between TTV infection and peptic ulcer. However, larger studies including surveys of the general population will be required to analyse the overall association between TTV and H. pylori.

Infection with TT virus, a novel transfusion-transmissible DNA virus, in haemophiliacs and in blood products.

We evaluated the characteristics and rate of infection with TT virus (TTV), a novel DNA virus, in Japanese haemophiliacs. TTV DNA was measured in 60 haemophiliacs by semi-nested polymerase chain reaction. Co-infection with hepatitis C virus (HCV), hepatitis G virus (HGV) and human immunodeficiency virus (HIV) was also evaluated. In addition, the rate of detection of TTV DNA in blood products was evaluated. TTV DNA was detected in 35/60 haemophiliacs (58.3%). There were no differences in the backgrounds or characteristics between haemophiliacs with and without TTV infection, except for higher levels of IgG and IgM in patients with TTV infection. In patients infected with TTV of types other than type 1, which are rarely detected in Japan, the rate of co-infection with HCV of imported types was high; TTV of types other than type 1 in Japanese haemophiliacs were probably transmitted by imported blood products. TTV DNA was detected in over half of the blood products tested, but TTV DNA concentrations in these products were lower than in the serum of haemophiliacs.

Interferon treatment of two patients with quadruple infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis G virus (HGV), and TT virus (TTV).

We administered interferon (IFN) to two patients who had quadruple infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis G virus (HGV), and TT virus (TTV), a recently isolated novel DNA virus. Nine mega-units of natural alpha-IFN were administered daily during the first two weeks and thrice weekly during the following 22 weeks (total dose, 720 mega-units). In both cases, serum alanine aminotransferase (ALT) levels decreased during IFN administration but increased thereafter. The concentrations of HCV, HIV, HGV, and TTV declined with the administration of IFN. However, the concentrations of these 4 viruses increased after the cessation of IFN with the except of TTV in patient 2 which disappeared during treatment and did not subsequently reappear. IFN reduced the concentrations of 4 viruses, in an apparently independent manner.

Low risk of TT virus (TTV) infection in medical workers.

The rate of infection with TT virus (TTV), a novel single-strand DNA virus was evaluated and the clinical and laboratory features in affected Japanese medical workers were analysed. TTV DNA was measured in 356 medical workers and in 150 age-matched controls using a seminested polymerase chain reaction. TTV DNA was detected in 62 of 356 medical workers (17.4%). There were no differences in the prevalence of TTV infection between medical workers and controls (18.9%) and in the characteristics of medical workers with TTV infection and medical workers without it, except that the mean age of patients with TTV infection was higher than that of patients without TTV. The medical workers were drawn from three groups: medical doctors, nurses and clinical laboratory technicians. There was no statistically significant difference between the rate of TTV infection in the three groups. These findings suggest that the risk of TTV infection in medical workers is low and not related to liver dysfunction.