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In 2018, there was a hepatitis A outbreak in Japan, and hepatitis A virus (HAV) infection is considered a sexually transmitted disease. In general, patients with hepatitis A should be given attention, and this disease should be prevented more than ever. The Japan Agency for Medical Research and Development (AMED) Hepatitis A and E viruses (HAV and HEV) Study Group has worked on the project to create "Recent Advances in Hepatitis A Virus (HAV) Research and Clinical Practice Guidelines for HAV Infection in Japan". The group consists of expert hepatologists and virologists who gathered at virtual meeting on August 5, 2023. Data about the pathogenesis, infection routes, diagnosis, complications, several factors for the severities, vaccination, and current and future treatments for hepatitis A were discussed and debated for a draft version. The participants assessed the quality of cited studies. The finalized recommendations are presented in this review. The recent advances in HAV research and clinical practice for HAV infection in Japan, have been reviewed by the AMED HAV and HEV Study Group. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common liver disease. It has a rapidly growing patient population owing to the increasing prevalence of obesity and type 2 diabetes. Patients with MASLD are primarily treated by family physicians when fibrosis is absent or mild and by gastroenterologists/hepatologists when fibrosis is more advanced. It is imperative that a system for the appropriate treatment and surveillance of hepatocellular carcinoma be established in order to ensure that highly fibrotic cases are not overlooked among the large number of MASLD patients. Family physicians should check for viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and drug-induced liver disease, and should evaluate fibrosis using NIT; gastroenterologists/hepatologists should perform liver biopsy, ultrasound elastography (260 units in Japan as of October 2023), and MR elastography (35 units in Japan as of October 2023). This review presents the latest findings in MASLD and the role, accuracy, and clinical use of NIT. It also describes the collaboration between Japanese primary care and gastroenterologists/hepatologists in Japan in the treatment of liver diseases, including MASLD. [ABSTRACT FROM AUTHOR]

Background: Hepatitis countermeasures are being promoted by governments in Japan. We aimed to develop performance indicators (PIs) to assess the process and outcome of such countermeasures implemented for the prevention of viral hepatitis-related liver cancer at the national and prefectural government levels. Methods: We developed 19 PIs for hepatitis countermeasures implemented by local governments, covering the morbidity and mortality of liver cancer, hepatitis testing, subsidy programs for examinations and antiviral treatment, and education on hepatitis patient care to healthcare workers. We analyzed the PIs for each prefecture from Fiscal Year (FY) 2018–2020. Results: The morbidity and mortality of liver cancer significantly decreased in the study period. The percentage of municipalities conducting hepatitis screening was already high at 95% in FY2017. The usage rate of government-subsidized screenings did not change. The subsidy usage rate for periodic viral hepatitis examination significantly increased. Meanwhile, the subsidy usage rate for antiviral treatment of hepatitis B increased, whereas that for hepatitis C decreased. The number of certified healthcare workers providing care for hepatitis patients increased significantly, and these workers were efficiently placed at regional core centers, institutions specialized in liver diseases, health care centers, and municipal governments. Liver cancer mortality was positively correlated with hepatitis screening, subsidies for periodic examinations, and the number of hepatitis medical care coordinators but was negatively correlated with subsidies for anti-HCV therapy, suggesting that rigorous countermeasures were implemented in prefectures with high liver cancer mortality. Conclusions: The developed PIs could be a useful tool for monitoring government efforts and achievements, thereby providing basic data for setting practical goals in liver cancer prevention. [ABSTRACT FROM AUTHOR]

Aim: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co‐infection from blood products for hemophilia has been a social problem in Japan, and liver transplantation (LT) for these patients has been a challenging procedure. However, with the advent of the direct‐acting antiviral agent for HCV and change in the policy for prioritization of deceased donor LT, the results of LT for patients co‐infected with HCV/HIV may have improved. Methods: This study was conducted to provide updated results of our nationwide survey of LT for patients co‐infected with HCV/HIV, from January 1997 to December 2019. We collected data on 17 patients with HIV/HCV co‐infection who underwent either deceased donor LT (n = 5) or living donor LT (n = 12). Results: All the patients were men with hemophilia, and the median age was 41 (range, 23–61) years. The median CD4 count before LT was 258 (range, 63–751). Most patients had poor liver function before surgery with Child–Pugh grade C and a Model for End‐stage Liver Disease score of 20 (range, 11–48). The right lobe was used for most grafts for living donor liver transplantation (n = 10). Overall survival was significantly better with a sustained viral response (SVR) than without an SVR, and a univariate analysis indicated that SVR after direct‐acting antiviral or interferon/ribavirin showed the highest hazard ratio for patient survival after LT. A multivariate analysis was not possible because of the limited number of cases. Conclusion: SVR for HCV showed the highest impact on the outcome of LT for patients with hemophilia co‐infected with HIV/HCV. SVR for HCV should be achieved before or after LT for patients with hemophilia co‐infected with HIV/HCV for a better outcome. [ABSTRACT FROM AUTHOR]

The incidence of hepatitis A virus (HAV) infection has declined significantly worldwide, including in Japan. A nationwide seroepidemiological study on hepatitis A in Japan has taken place almost every 10 years since 1973, and the last study was performed in 2003. In the present study, we describe the latest seroepidemiological pattern of hepatitis A in Japan using 7867 serum specimens obtained from healthy individuals collected between 2013 and 2017, approximately 10 years after the last study. Among them, 223 were anti‐HAV positive. About 68% of individuals aged 60 years and older had anti‐HAV antibodies, whereas only 1.1% of those aged below 60 years old had immunity; thus, almost all individuals younger than 60 years of age were HAV susceptible. In comparison with previous investigations, the susceptible population has increased and aged. According to data from the National Epidemiological Surveillance of Infectious Diseases (NESID) program, between 1989 and 2016, the proportion of patients with hepatitis A aged 60 years and older continuously increased with each year. The NESID data also suggested that recently, typical large foodborne outbreaks of hepatitis A have become rare, and cases tend to be reported among at‐risk groups; overseas travelers contributed to 25% of hepatitis A cases, and in 2018, the first nationwide hepatitis A outbreak that affected mostly men who have sex with men was reported. The purpose of this study was to determine the current status of HAV infection in Japan, based on both seroepidemiology and the national surveillance data from the NESID. [ABSTRACT FROM AUTHOR]

Background: We investigated the association between municipal socioeconomic deprivation levels and the positivity of hepatitis B surface antigen (HBsAg) and the prevalence of hepatitis C virus (HCV) among individuals who have never participated in hepatitis screening using Japanese national screening data.Methods: The hepatitis virus screening data analyzed included the 5-year age group-specific number of participants aged 40 years or older, number of HBsAg-positive persons, and number of HCV carriers for each municipality from 2013 to 2017. Principal component analysis was used to derive a socioeconomic deprivation level using the socioeconomic characteristics of municipalities. Bayesian spatial Poisson regression analysis was conducted to investigate the association between the socioeconomic deprivation level and the results of screening. Data on 1,660 municipalities were used in the analysis.Results: The data of 4,233,819 participants in the HBV screening and 4,216,720 in the HCV screening were used in the analysis. A principal component interpreted as level of rurality (principal component 1) and another principal component interpreted as level of low socioeconomic status among individuals (principal component 2) were extracted as the major principal components. Their principal component scores were used as the deprivation levels of municipalities. Spatial regression analysis showed that the deprivation level derived from the sum of the scores of principal components 1 and 2 was significantly and positively associated with HBsAg positivity and HCV prevalence. In addition, the deprivation level derived only from the score of principal component 2 was also significantly and positively associated with the outcomes. Conversely, the deprivation level derived only from the score of principal component 1 was not associated with the outcomes. Moreover, population density was significantly and positively associated with HBsAg positivity and HCV prevalence.Conclusions: This study suggested that participation in hepatitis virus screening is important and meaningful, particularly for areas with a higher lower socioeconomic level in Japan. [ABSTRACT FROM AUTHOR]

Background and Aim: With the control of viral hepatitis, alcoholic hepatocellular carcinoma (HCC) is becoming increasingly important in Japan. In alcoholic cirrhosis, the impact of portal hypertension is significant. Thus, it may be difficult to predict prognosis accurately with the reported prognostic scores. Here we propose the platelet‐albumin‐bilirubin tumor nodes metastasis (TNM) score (PALBI‐T score) as a prognostic model for HCC in alcoholic liver disease, and investigate its usefulness. The PALBI‐T score is an integrated score based on the TNM stage and PALBI grade including platelets, reflecting portal hypertension. Methods: This study included 163 patients with alcoholic HCC treated at our Center from 1997 to 2018. We compared the prognostic prediction abilities of the Japan Integrated Staging (JIS) score, ALBI‐T score, and PALBI‐T score. The PALBI‐T score was calculated similarly to the JIS and ALBI‐T scores. Areas under the receiver operating characteristic curve (AUC) were calculated for predicting overall survival (OS). Results: In predicting the 1‐year survival, the JIS score had a larger AUC (AUC = 0.925) than the ALBI‐T score (AUC = 0.895) and PALBI‐T score (AUC = 0.891). On the other hand, there was no significant difference in predicting OS among the integrated scores. The PALBI‐T score (AUC = 0.740) had the largest AUC, and the JIS score (AUC = 0.729) and ALBI‐T score (AUC = 0.717) were not significantly different from the PALBI grade (AUC = 0.634). The PALBI grade reflected the degree of portal hypertension. Conclusion: In patients with alcoholic HCC, the Japan Integrated Staging score is useful for predicting short‐term prognosis. The PALBI‐T score, which reflects portal hypertension, appears to be a more valid prognostic score for predicting long‐term prognosis. [ABSTRACT FROM AUTHOR]

Background: A hepatitis A epidemic occurred among men who have sex with men (MSM) in Japan in 2017–2018. In this study, we employ a parsimonious mathematical model to epidemiologically investigate the dynamics of infection, aiming to evaluate the effectiveness of campaign-based interventions among MSM to raise awareness of the situation. Methods: A mathematical model describing a mixture of human-to-human transmission and environmental transmission was fitted to surveillance data. Taking seasonally varying environmental transmission into account, we estimated the reproduction number of hepatitis A virus during the course of epidemic, and, especially, the abrupt decline in this reproduction number following campaign-based interventions. Results: The reproduction number prior to the countermeasures ranged from 2.6 to 3.1 and then began to decrease following campaign-based interventions. After the first countermeasure, the reproduction number decreased, but the epidemic remained supercritical (i.e., Rt > 1). The value of Rt dropped well below one following the second countermeasure, which used web articles to widely disseminate information about the epidemic risk. Conclusions: Although the effective reproduction number, Rt, changes because of both intrinsic and extrinsic factors, the timing of the examined countermeasures against hepatitis A in the MSM population was consistent with the abrupt declines observed in Rt. Even without vaccination, the epidemic was brought under control, and risky behaviors may have been changed by the increase in situation awareness reached through web articles. [ABSTRACT FROM AUTHOR]

Background and Aim: The current prevalence of hepatitis C virus infection and hepatitis C virus‐associated mortality in Japan falls short of the World Health Organization goal of viral hepatitis elimination by 2030. We aimed to evaluate the trends in hepatitis C virus‐associated mortality in Japan. Methods: This nationwide observational study used the Japanese Vital Statistics from 1998 to 2017 and included all Japanese hepatitis C virus‐associated deaths (84 936) of adults aged ≥ 40 years. We calculated the crude and age‐standardized mortality rates per 100 000 persons by age and sex. Joinpoint regression analysis was used to identify significant changing points in trends and to estimate the annual percentage changes and the average annual percentage changes for the entire study period. Results: The crude mortality rate per 100 000 persons (annual death number) increased from 5.5 (3548) in 1998 to 7.0 (4843) in 2005 and decreased to 4.0 (3095) in 2017. By 2017, the crude mortality rates per 100 000 persons among men and women had dropped to 3.6 and 4.3, respectively. The age‐standardized mortality rate was higher in women than in men. The average annual percentage change was −3.8% (95% confidence interval: −5.0 to −2.5). The declining trend was more rapid in men (−4.5%, 95% confidence interval: −5.3 to −3.6) than in women (−2.7%, 95% confidence interval: −3.8 to −1.6). Conclusions: Trends in hepatitis C virus‐associated mortality rates have declined in an accelerating manner in Japan, especially among men. [ABSTRACT FROM AUTHOR]

Background and Aim: CT‐P13, an infliximab (IFX) biosimilar, was approved for treatment of inflammatory bowel disease. However, no comparison with the originator IFX in this indication has been conducted in Japan where endemic levels of tuberculosis and hepatitis virus infection are not low. We evaluated the safety and efficacy in real‐world data of CT‐P13 and compared with originator IFX data in Japan. Methods: In a prospective post‐marketing surveillance (PMS) study, patients who received CT‐P13 in a 28‐month period from January 2015 were followed up for 2 years. By conducting Japanese administrative database search (DBS) for the same period of PMS, data of the originator IFX including treatment persistence, tuberculosis incidence, and liver injury were analyzed retrospectively and compared with the corresponding PMS data of CT‐P13. Results: CT‐P13 persistence in PMS (n = 640) and IFX persistence in DBS (n = 4113) were almost similar between patients who switched from the originator and patients who continued on the originator, and also between the biologics‐naïve patient groups. There were no differences in the incidences of tuberculosis and hepatic injury (Tuberculosis: 2 patients [0.31%] with CT‐P13, 10 patients [0.24%] with the originator, P = 0.75; Hepatic injury: 18.5% with CT‐P13, 15.4% with the originator, P = 0.22). Most of the patients with hepatic injury continued treatment in PMS and DBS at similar rates (80.8% vs 83.6%, P = 0.65). Conclusion: The results of long‐term PMS of CT‐P13 compared with external reference data from an administrative database suggested that the biosimilar and its originator were comparably useful in real‐world clinical practice. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Liver disease is characterized by the progression from hepatitis to cirrhosis, followed by liver cancer, i.e., a disease with a higher mortality rate as the disease progresses. To estimate the cost of illness (COI) of liver diseases, including viral hepatitis, cirrhosis, and liver cancer, and to determine the overall effect of expensive but effective direct-acting antivirals on the COI of liver diseases. Patients or materials and methods: Using a COI method from available government statistics data, we estimated the economic burden at 3-year intervals from 2002 to 2017. Results: The total COI of liver diseases was 1402 billion JPY in 2017. The COI of viral hepatitis, cirrhosis, and liver cancer showed a downward trend. Conversely, other liver diseases, including alcoholic liver disease and nonalcoholic steatohepatitis (NASH), showed an upward trend. The COI of hepatitis C continued to decline despite a sharp increase in drug unit prices between 2014 and 2017. Conclusions: The COI of liver diseases in Japan has been decreasing for the past 15 years. In the future, a further reduction in patients with hepatitis C is expected, and even if the incidence of NASH and alcoholic liver disease increases, that of cirrhosis and liver cancer will likely continue to decrease. [ABSTRACT FROM AUTHOR]

Despite the growing momentum created by the WHO for eliminating viral hepatitis as a public health threat by 2030, the global response is still slow and more actions are needed to meet the elimination goals, especially in low-income and middle-income countries. Japan is one of a handful of countries currently on track to achieve the WHO hepatitis elimination targets by 2030. To better understand the successful control of viral hepatitis in Japan, it is important to recognize the role of the patient association for viral hepatitis, known as the "Japan Hepatitis Council", which celebrates its 50th anniversary in 2021. The greatest impact of the Japan Hepatitis Council has been in achieving wider access to antiviral treatments for viral hepatitis. The example of Japan and the Japan Hepatitis Council highlights the need for the engagement of civil society and patient groups to ensure equitable access to hepatitis services and to accelerate the global hepatitis elimination. [ABSTRACT FROM AUTHOR]

Background: To assess the recent real-world changes in the etiologies of liver cirrhosis (LC) in Japan, we conducted a nationwide survey in the annual meeting of the Japan Society of Hepatology (JSH).Methods: We investigated the etiologies of LC patients accumulated from 68 participants in 79 institutions (N = 48,621). We next assessed changing trends in the etiologies of LC by analyzing cases in which the year of diagnosis was available (N = 45,834). We further evaluated the transition in the real number of newly identified LC patients by assessing data from 36 hospitals with complete datasets for 2008-2016 (N = 18,358).Results: In the overall data, HCV infection (48.2%) was the leading cause of LC in Japan, and HBV infection (11.5%) was the third-most common cause. Regarding the transition in the etiologies of LC, the contribution of viral hepatitis-related LC dropped from 73.4 to 49.7%. Among the non-viral etiologies, alcoholic-related disease (ALD) and nonalcoholic steatohepatitis (NASH)-related LC showed a notable increase (from 13.7 to 24.9% and from 2.0 to 9.1%, respectively). Regarding the real numbers of newly diagnosed patients from 2008 to 2016, the numbers of patients with viral hepatitis-related LC decreased, while the numbers of patients with non-viral LC increased.Conclusions: HCV has remained the main cause of LC in Japan; however, the contribution of viral hepatitis as an etiology of LC is suggested to have been decreasing. In addition, non-viral LC, such as ALD-related LC and NASH-related LC, is suggested to have increased as etiologies of LC in Japan. [ABSTRACT FROM AUTHOR]

Background and Aim: The incidence of acute hepatitis A [AH (A)] is decreasing because of improvements in hygiene; however, cases of sporadic severe hepatitis are still being reported. We assessed the epidemiology of AH (A) in Japan. Methods: This was a hospital‐based retrospective study, in which 126 AH (A) patients (96 men [76%], median age 39 [range, 19–66] years) were enrolled. Patients diagnosed with AH (A) before 2001 (n = 79) and after 2001 (n = 47) were compared. Results: The incidence of AH (A) showed peaks in 1990, 1999, and 2018. After 2001, one patient had hepatitis B virus, four had human immunodeficiency virus, and three had syphilis coinfections. Before and after 2001, HAV was transmitted, respectively, by raw oysters (28% and 26%), overseas travel (19% and 28%), and sexual contact (0% and 19%) (P < 0.01). The frequencies of symptoms were appetite loss (51% and 32%), fever (63% and 81%), and diarrhea (3% and 13%) (all P < 0.05), respectively. On admission, the median levels of alanine aminotransferase (1455 and 3069 U/L) and γ‐glutamyl transpeptidase (221 and 345 U/L) were significantly higher (P < 0.01), and the prothrombin time (77.5% and 65.9%) and platelet count (22.7 and 16.4 × 10/μL) were significantly lower after 2001 (P < 0.05). A time to normalization of the bilirubin level ≥ 30 days was associated with older age and a diagnosis of AH (A) after 2001. Conclusions: Outbreaks and severe AH (A) cases due to sexual transmission have been reported recently. It is necessary to examine their sexual behavior and other sexual infection. [ABSTRACT FROM AUTHOR]

Aim: A nationwide survey of acute liver failure (ALF) and late‐onset hepatic failure (LOHF) has revealed that the outcomes of recent patients whose diseases were caused by infection with hepatitis A virus (HAV) have worsened, compared with those of previously reported patients. The factors associated with this deterioration were evaluated. Methods: A total of 83 patients with HAV infection seen between 1998 and 2015 were enrolled. All the patients had a prothrombin time–international normalized ratio of 1.5 or more and hepatic encephalopathy of grade 2 or more severe. The demographic and clinical features of 45 patients seen prior to 2003 (cohort 1) and 38 patients seen during 2004 and thereafter (cohort 2) were compared. Results: Three and four patients in cohort 1 and cohort 2, respectively, received liver transplantations; the survival rates among the remaining patients were 56% for cohort 2 and 79% for cohort 1 (P < 0.05). The mean age (±standard deviation) of the patients was higher in cohort 2 than in cohort 1 (58 ± 11 vs. 48 ± 13 years; P < 0.01). The percentages of patients with underlying metabolic diseases were 22% in cohort 1 and 61% in cohort 2 (P < 0.01). Diabetic mellitus was more common among deceased patients than among rescued patients (29% vs. 8%; P < 0.05) among patients who did not receive liver transplantations, and a multivariate analysis revealed that patient age and disease type were significantly and independently associated with the outcome. Conclusion: The outcomes of recent patients with ALF or LOHF caused by HAV infection have recently worsened mainly because of an increase in underlying metabolic diseases as a consequence of aging. [ABSTRACT FROM AUTHOR]

Aim: Ongoing hepatitis A outbreaks among men who have sex with men (MSM) have been reported worldwide, mainly in Europe, since 2016. In Japan, there has been an increase in the number of notified hepatitis A cases since January 2018, most of which were suspected to have been transmitted through homosexual contact. In this paper, we describe the current outbreak situation of hepatitis A among MSM. Methods: Between March and July 2018, 13 cases of hepatitis A were identified in our hospital. All cases were identified as MSM. Data on clinical and laboratory findings and therapies were collected from medical records. Serum or stool samples were obtained from 13 patients and subjected to sequence analysis. Results: Of all patients, 12 reported to have male‐to‐male homosexual contact within 7 weeks prior to symptom onset, and 6 visited sex‐on‐premises venues in the same area. Furthermore, 12 patients were infected with HIV and consequently received antiretroviral therapy with sustained viral suppression. Ten patients received pulsed methylprednisolone therapy. Plasma exchange was additionally carried out in one patient. All patients received inpatient hospital care and were discharged alive. Sequence information, which was available in all cases, showed that the hepatitis A virus strain was identical to the EuroPride strain (RIVM‐HAV16–090). Conclusions: Results of sequence analysis suggest that the ongoing hepatitis A outbreak among MSM in Japan is linked to the 2016 European outbreaks. A vaccination program is urgently required for high‐risk populations to control this ongoing outbreak. [ABSTRACT FROM AUTHOR]

Aim: The major transmission mode of hepatitis A virus (HAV) in Japan is the fecal–oral route by contaminated foods. In contrast, HAV infection is well documented as a sexually transmitted disease in Europe and North America. The present study was undertaken to determine the full‐genome sequence of HAV and trace the transmission route of HAV in Japanese men who have sex with men (MSM). Methods: In 2018, we encountered three Japanese MSM with acute hepatitis A co‐infected with HIV for 4–12 years. Serum samples obtained from these patients were used for HAV full‐genome analyses. Results: Isolated HAV strains were segregated into subgenotype IA. The three HAV strains shared 100% identity within the 481‐nucleotide partial sequence. The entire nucleotide sequence showed that the three strains were 99.97% similar to each other with only two nucleotide substitutions. At the amino acid level, the three strains differed from each other by only one or two amino acids. All three strains obtained in the present study were >99.6% identical to the 66 reported strains isolated from Taiwan and European countries during 2015–2017. In addition, these 66 strains include the RIVM‐HAV16‐090 (EuroPride) strain, which has been involved in HAV outbreaks among MSM worldwide. Conclusions: We determined for the first time the full‐genome sequence of HAV isolated from Japanese MSM with acute hepatitis A and found that the strains were identical to those from MSM worldwide. Thus, these HAV strains were imported to Japan from foreign countries through MSM. [ABSTRACT FROM AUTHOR]

Background: A nationwide survey was performed to clarify the recent status of acute liver failure (ALF) and late-onset hepatic failure (LOHF) in Japan.Methods: Two-step surveys for patients with ALF and LOHF meeting the Japanese diagnostic criteria were performed annually in 782 hospitals. The clinical features of the patients were then compared to those reported in previous surveys.Results: In total, 1554 and 49 patients with ALF and LOHF, respectively, who were seen between 2010 and 2015 were enrolled. The subjects were classified into 1280 patients with hepatitis (642 non-comatose and 638 comatose) and 323 patients without hepatitis (190 non-comatose and 133 comatose). Compared with patients seen between 1998 and 2009, an older patient age and a higher percentage of underlying extrahepatic disease were observed. Although hepatitis virus infection was the most frequent etiology, the percentage of patients with this etiology had decreased, compared with previous cohorts, while the percentages of patients with drug-induced liver injuries, autoimmune hepatitis, and an indeterminate etiology had increased. Liver transplantation was performed in 170 patients (10.6%), whereas artificial liver support with plasmapheresis and/or hemodiafiltration were performed for most of the comatose patients. The outcomes of comatose patients were unfavorable, similar to previous surveys, especially the outcomes of hepatitis B virus carriers, including those with de novo hepatitis B (survival rate of 5.4% without liver transplantation).Conclusion: Although the clinical features, including the etiologies, of patients with ALF and LOHF have changed, the outcomes of patients have not improved in recent years. [ABSTRACT FROM AUTHOR]

Background: In Japan, health checkups for workers are legally compulsory. Considering legal health checkup items are important for Japanese workers' health problems. To date, the legal health checkup items for blood cell counts include only red blood cell counts and hemoglobin but not platelet counts. This study aimed to investigate the significance of measuring platelets in workers by showing the association between the FIB-4 index (FIB-4), which can be easily calculated from factors including platelet counts and viral hepatitis infection., Method: Both cross-sectional and longitudinal analyses were conducted on the comprehensive medical examinations of male workers. In fiscal year (FY) 2019, a logistic regression model was applied to 12,918 examinees. For 13,459 examinees (mean age = 47.5 ± 9.3 SD), FY2000 was set to be followed until FY2019. A total of 149,956 records between FY2000 and FY2019 were analyzed cross-sectionally, and 8,038 men who were consecutively examined to FY2019 at the longest were analyzed longitudinally. Receiver operating characteristic (ROC) curve-area under the ROC curve (ROC-AUC) and Cox proportional methods were used to examine the association between platelet-related indices and viral hepatitis infection., Results: Logistic regression showed that the risk of FIB-4 ≥ 2.67 was mostly associated with hepatitis C virus antibody (HCVAb) positivity [odds ratio (OR) = 2.51, 95% confidence interval (CI) = 1.08-5.86], while negatively associated with body mass index (BMI) (OR = 0.54, 95% CI = 0.30-0.97), and not associated with the presence of fatty liver. To detect HVC Ab positivity, ROC-AUC showed more effectiveness in FIB-4 than in the AST/ALT ratio (0.776, 95% CI = 0.747-0.773 vs. 0.552; 95% CI = 0.543-0.561). The Cox analysis showed that the risk of FIB-4 ≥ 2.67 was closely associated with hepatitis B virus surface antigen (HBsAg) [hazard ratio (HR) = 3.1, 95% CI = 2.0-4.6] and HCV Ab positivity (HR = 3.2, 95% CI = 2.0-5.0)., Conclusion: Our results suggest that it might be worth considering that usage of information on platelets in legal health checkups could be some help not to overlook workers with hepatitis virus carriers as a complementary countermeasure, although further investigations are needed into its practical application., Competing Interests: TH was employed by Occupational Hygiene and Promotion Center, Hitachi Ltd., Tokyo, Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kasuya, Fukai, Watanabe, Furuya, Nakazawa, Honda, Hayashi, Nakagawa, Tatemichi and Korenaga.)

Background and Aims The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. Methods Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. Results Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. Conclusions The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients. [ABSTRACT FROM AUTHOR]

Objective: Although liver biopsy is the gold standard for viral liver disease management, it is invasive and the sampling error rate is problematic. Real-time tissue elastography (RTE), a recently developed method of ultrasound elastography, can be used to assess liver fibrosis noninvasively but the overlap between fibrosis stages limits its ability to assess liver fibrosis adequately when used alone. Methods: A multicenter collaborative study involving 542 patients with chronic viral hepatitis and cirrhosis who were scheduled to undergo liver biopsy compared the image features obtained from RTE image analysis, the liver fibrosis index (LFI), and pathological diagnosis. RTE and a blood test were performed on the same day as the liver biopsy. Data mining was also performed to construct a decision tree, and its diagnostic performance for assessing liver fibrosis was evaluated. Results: The LFI was higher in patients with chronic hepatitis C (CHC) than in those with chronic hepatitis B (CHB). When a decision tree was constructed by data mining of RTE and serological findings, the diagnostic accuracy was very high for all fibrosis stages, with respective rates at F1, F2, F3, and F4 of 94.4, 54.1, 38.7, and 81.3% for patients with CHC and of 97.1, 50.0, 43.8, and 80.6% for patients with CHB. Conclusions: The variation in LFI values between the different etiologies appears to reflect the difference in the development style of liver fibrosis. The decision tree for assessing liver fibrosis constructed by data mining of both RTE and serological findings had a high diagnostic performance in assessing liver fibrosis and shows promising clinical utility. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim To summarize the annual nationwide survey on fulminant hepatitis ( FH) and late-onset hepatic failure ( LOHF) between 2004 and 2009 in Japan. Methods The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals. Results Four hundred and sixty ( n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus ( HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation ( LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF. Conclusion The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved. [ABSTRACT FROM AUTHOR]

Background The biomarkers of excessive alcohol intake reported thus far have not always been reliable. We discovered the presence of free glycerol (FG) by high-performance liquid chromatography (HPLC) in the serum of alcoholic patients but not in healthy persons, and a higher percentage of the alcoholics were positive for serum FG than for gamma-glutamyl transpeptidase, mean corpuscular volume, or carbohydrate-deficient transferrin (%CDT). Therefore, in this study, we investigated whether the same results as with HPLC could be obtained by measuring FG with an easy-to-use autoanalyzer and whether the serum FG measured by this method would be useful as a biomarker of excessive alcohol intake. Methods First, the measurements of serum FG made by HPLC and by a biochemical method with an autoanalyzer were tested for a correlation, and then fasting serum FG was measured with the autoanalyzer in 3 groups: a group of Japanese male alcoholics who drank until just before admission, a group of Japanese male patients with chronic viral hepatitis, and a group of Japanese healthy male volunteers. Results There was a strong positive correlation between the serum FG values measured by HPLC and by the autoanalyzer in the alcoholic group. The values in the alcoholic group were significantly higher than in the viral hepatitis group and healthy control group. We set the cutoff serum FG value for discriminating between the alcoholic group and the other 2 groups in the receiver operating characteristic analysis at 0.9 mg/dl, and that cutoff value provided a sensitivity of 80% for identifying the alcoholic group and a specificity of 84 and 94% in relation to the viral hepatitis group and the healthy volunteer group, respectively. Among various clinical tests in the alcoholic group, serum FG showed the highest rate of abnormally high value. Conclusions Measurement of serum FG with an autoanalyzer may be useful as a biomarker of excessive alcohol intake. [ABSTRACT FROM AUTHOR]

Aim: Recently, the number of foreigners living in Japan has been increasing, with the majority originating from China. It is important for us to know the prevalence of hepatitis virus markers among them, as proper medical practices and vaccinations should be prepared when seeing them and their offspring. Methods: We examined the relationship between the prevalence of hepatitis virus markers: hepatitis B surface antigen (HBsAg), anti-HBs, anti-hepatitis C virus (HCV), anti-hepatitis A virus (HAV) and anti-hepatitis E virus immunoglobulin (Ig)G, and background such as age, birthplace and length of stay in Japan, of 568 Chinese residing in Tokyo, and also of 55 indigenous Japanese. Results: The prevalence of HBV and HAV markers in Chinese staying in Tokyo is higher than in indigenous Japanese (HBsAg, 10% vs 1.8%; anti-HBs, 45% vs 9.0%; anti-HAV, 90% vs 14%). There were no differences in anti-HCV and anti-HEV IgG between the two groups. Conclusion: Indigenous Japanese subjects have less immunity against HAV and HBV. The HBV carrier rate is higher in Chinese subjects, and attention should be paid to this issue in clinical practice. It might be important to control hepatitis viruses in Chinese subjects when doctors see them in Japan. [ABSTRACT FROM AUTHOR]

Background & Aims: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. Methods: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12weeks along with PEG-IFN and RBV for 24weeks (Group A), while 63 to PEG-IFN and RBV for 48weeks (Group B). Results: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p =0.0020). Conclusions: Although the triple therapy with telaprevir-based regimen for 24weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required. [ABSTRACT FROM AUTHOR]

Advanced chronic hepatitis C patients with sustained virolological response by antivirals remain at risk for hepatocellular carcinoma (HCC). We investigated the incidence of HCC during and immediately after peginterferon-alfa-2a and ribavirin (RBV) treatment in patients with chronic hepatitis C in Japan. HCC was detected in 8 of 238 patients during and after these treatments (mean follow-up period: 572 ± 252 days). In conclusion, occurrence of HCC is not a rare event during and immediately after peginterferon-alfa-2a plus RBV treatment. In cases with cirrhosis, higher α-fetoprotein levels, old age, or a previous history of HCC treatment, clinicians should be especially alert for the possible development of HCC during and immediately after peginterferon-alfa-2a and RBV treatment. Clinicians should regularly check for the possible development of HCC even in chronic hepatitis C patients under treatment. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Acute liver failure in Japan usually consists of fulminant hepatitis (FH) due to viral infection, autoimmune hepatitis and drug-allergy-induced liver injury. The annual incidence of FH was estimated at 429 cases in 2004. FH is classified into acute or subacute type, and the prognosis of the latter is poor. Hepatitis B virus (HBV) is the most frequently identifiable agent that causes FH in Japan. Transient HBV infection is more prevalent in the acute than subacute type, whereas the frequency of HBV carriers is greater in the subacute type. FH due to HBV reactivation from resolved hepatitis B has been increasingly observed in patients with malignant lymphoma treated with rituximab and corticosteroid combination therapy. The prognosis is poor in HBV carriers with acute exacerbation, especially in patients with HBV reactivation from resolved hepatitis B. Despite careful investigation, the etiology is still unknown in 16% and 39% of the acute and subacute type of FH, respectively. Autoimmune hepatitis and drug-allergy-induced liver injury are found in 7% and 10%, respectively, and are more frequently observed in the subacute type of FH. Living donor liver transplantation is now the standard care for individuals with poor prognosis. Artificial liver support with plasmapheresis and hemodiafiltration plays a central role while waiting for a donor liver or for the native liver to regenerate. Further research is necessary to identify the causes of unknown origin. In addition, to improve the prognosis of FH, it is necessary to establish treatment modalities that are effective for liver regeneration. [ABSTRACT FROM AUTHOR]

A 12-year-old Japanese boy suffered from severe acute hepatitis and pancytopenia. The patient underwent successful bone marrow transplantation from an HLA-identical sister. Torque teno virus (TTV) DNA of genotype 1a and IgM-class antibody against the virus were detected in sera at the onset of hepatitis. TTV/1a DNA and anti-TTV/1a IgM antibody levels were undetectable on the 16th and 46th days after the onset of illness, respectively. Anti-TTV/1a IgG antibody was positive throughout the observation period. Sequential viral load and anti-TTV/1a IgM antibody suggested a primary infection of TTV/1a. Genomic sequence of the virus coincided with that of the original strain first isolated from human. TTV DNA was quantified at 130 copies in 10(5) bone marrow mononuclear cells, which suggested that infection of hematopoietic cells might be the cause of aplasia. This is the first report of TTV hepatitis-associated aplastic anemia assessed by the anti-TTV antibodies and viral load in peripheral blood and bone marrow. [ABSTRACT FROM AUTHOR]

In this study, 520 serum samples from Yezo-deer in the Hidaka district, Hokkaido, Japan were examined by enzyme-linked immunosorbent assay to investigate whether the animals were infected with hepatitis E virus (HEV). The distribution of optical density values showed a bimodal pattern and 181 samples (34.8%) were deemed to be antibody-positive against HEV. At least five (2.8%) of the positive sera gave specific bands by Western blot analysis. An age-dependent increase in prevalence of the antibodies was found among the animals. These findings indicate that Yezo-deer are a possible host for HEV infection. To avoid the risk of becoming HEV infected, the consumption of raw Yezo-deer meat must be prohibited. [ABSTRACT FROM AUTHOR]

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because onefourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed. [ABSTRACT FROM AUTHOR]

Background and Aim: The characteristics and prognosis of patients with hepatitis virus marker-negative hepatocellular carcinoma (HCC) is not fully elucidated in Japan. We investigated the characteristics and prognosis of HCC patients in whom no markers for hepatitis virus infection were detected, in comparison with those of HCC patients with hepatitis virus infection. Methods: Viral markers for hepatitis B and C virus (HBV and HCV) infection were measured in 1152 patients in whom initial HCC was diagnosed between 1991 and 2004. Patient characteristics, characteristics of HCC and survival were compared between patients in whom no marker was positive (viral marker-negative HCC) and those in whom chronic HBV or HCV infection was confirmed by viral markers (viral HCC). Results: Overall, 119 patients (10.3%) were shown to have viral marker-negative HCC. Hepatocellular carcinoma was detected under surveillance in a significantly smaller percentage of patients with viral marker-negative HCC than of patients with viral HCC ( P < 0.0001). The tumor was significantly larger ( P < 0.0001) and vascular invasion was significantly more prevalent ( P = 0.0003) in patients with viral marker-negative HCC than in those with viral HCC. The survival rate of patients with viral marker-negative HCC was significantly lower than that of patients with viral HCC ( P = 0.0378). Conclusion: The patients with HCC in whom hepatitis viral infection had not been confirmed tended not to be under surveillance, resulting in the detection of HCC at more advanced stage and with a poorer prognosis. Efforts to identify patients without hepatitis virus infection who should be under surveillance for HCC will be necessary in the future. [ABSTRACT FROM AUTHOR]

Background: In Japan, patients with hepatitis C virus (HCV)-associated liver disease are getting older, and thus the number of deaths due to such disease is increasing. The efficacy of combination therapy with ribavirin and interferon for chronic HCV infection in elderly patients has not been fully clarified. The aim of the present study was to evaluate the efficacy and tolerability of combination therapy in such patients. Methods: Two hundred and twenty consecutive patients with chronic hepatitis C were treated with combination therapy. These patients were divided into two groups according to age: patients ≥ 60 years ( n = 66) and patients < 60 years ( n = 154). Clinical characteristics, the sustained virologic response (SVR) rate obtained by intention-to-treat analysis, and the rate of reduction or discontinuation of ribavirin were compared between the two groups. Results: The ribavirin discontinuation rate was significantly higher in the patients aged ≥60 years than in the patients aged <60 years. However, the SVR rates did not differ significantly between patients aged ≥60 years and those aged <60 years (31.8% vs 38.3% by intention-to-treat analysis). According to multivariate analysis, genotype and HCV viral load were significantly associated with SVR while patient age did not affect SVR. Conclusions: Treatment of chronic hepatitis C with combination therapy was comparably effective between patients aged ≥60 years and those aged <60 years, although the ribavirin discontinuation rate was higher among the older patients than the younger patients. [ABSTRACT FROM AUTHOR]

We examined 976 sika deer serum samples, 159 liver tissue samples and 88 stool samples collected from 16 prefectures in Japan, and performed ELISA and RT-PCR assays to detect antibodies to HEV and HEV RNA, respectively. Although 25 (2.6%) of 976 samples were positive for anti-HEV IgG, the antibody titers were very low. The OD values ranged between 0.018 and 0.486, forming a single distribution rather than a bimodal distribution, suggesting that the antibody detected in this study was not induced by HEV infection, or that deer have low sensitivity to HEV. HEV RNA was not detected in these samples, also suggesting that deer may not play a role as an HEV reservoir. [ABSTRACT FROM AUTHOR]

Aims: Transmission of hepatitis E virus (HEV) from wild boar to humans has been reported, particularly from Japan. We attempted to clarify this issue. Methods: We assessed the IgG class antibodies against HEV (anti-HEV) in serum samples taken from 406 boar living in the Ehime area of western Japan from 2001 to 2004, of which 392 were captured in the wild (wild-caught boar) and 14 had been kept in a breeding farm (bred boar). Results: Anti-HEV positive rate in the bred boar (10/14, 71.4%) was significantly higher than in the wild-caught boar (100/392, 25.5%) ( P < 0.001). Of the 392 wild-caught boar, 12 (3.1%) were positive for HEV-RNA, 10 of which were then subjected to phylogenetic analyses by sequencing an 821-nt fragment within ORF1. All the 10 isolates segregated to genotype 3, and eight of them were mutually related to form a cluster. All the eight HEV isolates in this cluster were from the wild-caught boar living in one and the same habitat within the studied area, while the other two independent isolates were from different regions. Conclusion: HEV infection is endemic in wild boar in the Ehime area, and we should regard the wild boar as an important reservoir of HEV. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis E virus (HEV), a single-strand RNA virus, has been recovered not only from human beings but also from various species of animals. Here we report our results suggesting that mongoose should be added to the list of reservoir animals of HEV. Of 100 mongooses we examined in Okinawa, Japan, 21 were thought to be positive for anti-HEV antibodies, among which one was definitely positive for HEV RNA. Full-genome sequencing of the HEV isolate revealed that it segregates to a unique subgroup within genotype III. Interestingly, this mongoose strain was closely related to a swine isolate previously reported from Okinawa, implicating the possibility of interspecies transmission between these animals. [Copyright &y& Elsevier]

Hepatitis B or C infection has been major cause of chronic liver disease (CLD) in Japan. The percentages of patients of hepatitis B (8.7%, to 21.3%), alcoholic (0.3% to 5.9%) or NAFLD (0.1% and 2.9%) were increased, whereas that of hepatitis C was decreased (45.5% to 33.7%) from 2008 to 2018. The mean age of patients with hepatitis B (57.9 to 63.6), hepatitis C (65.5 to 70.0) hepatitis B and C (62.8 to 66.6) autoimmune (62.6 to 66.4) or alcoholic (59.2 to 64.4) was getting older from 2008 to 2018. [Extracted from the article]

Background. The Japan integrated staging (JIS) score is recognized to be useful in managing hepatocellular carcinoma (HCC). We evaluated the effects of the causative virus in patients stratified by this system. Methods. We compared clinicopathologic features, cumulative and tumor-free survival rates, and causes of death between 301 hepatitis C virus-positive patients (HCV group) and 60 hepatitis B virus-positive patients (HBV group). Results. Among patients with low JIS scores (0 or 1), the proportions of patients with high aspartate and alanine aminotranferase activities, moderate-to-severe active hepatitis, and with cirrhosis were significantly higher in the HCV than in the HBV group. Among patients with high JIS scores (2 to 4), the proportion with moderate-to-severe active hepatitis was also significantly higher in the HCV group. In patients with low JIS scores, those in the HCV group had significantly lower tumor-free and cumulative survival rates than those in the HBV group. Although no patient in the HBV group died of causes other than liver disease (HCC or hepatic failure), some patients in the HCV group died of causes other than liver disease. The proportion of patients who died because of HCC recurrence tended to be higher among patients with high JIS scores than among patients with a low JIS score. Conclusions. The effects of viral status on survival outcomes are greatest in patients with JIS scores of 0 or 1. [ABSTRACT FROM AUTHOR]

Background: The association between hepatitis C virus (HCV) and oral lichen planus (OLP) is more common in the Mediterranean area and Japan, possibly because of immunogenetic factors. Methods: Intermediate-resolution HLA-DRB typing by hybridization with oligonucleotide probes was performed in 31 Italian OLP patients with HCV infection, in 45 Italian OLP and in 48 British OLP patients without HCV infection. As healthy controls we included data from 145 unrelated Italian and 101 unrelated British bone marrow donors. Results: Italian HCV+ve OLP patients possessed the HLA-DR6 allele more frequently than Italian and British OLP patients without HCV infection (51.6% vs. 17.7% vs. 16.7%; P corrected = 0.028 and 0.017, respectively). There was no difference in the frequency of the HLA-DR6 allele between Italian and British control subjects. Conclusions: The present data suggest that HLA-DR6 may be responsible for the peculiar geographic heterogeneity of the association between HCV and OLP. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP), an immune-mediated disorder, has been reported as an extra-hepatic manifestation of Hepatitis C virus (HCV) infection, especially in HCV hyperendemic areas such as southern Europe and Japan. The aim of this study was to investigate from an epidemiological standpoint whether HCV infection is an important factor affecting the relative risk of OLP in a Mediterranean population or whether this relates to the degree of HCV endemicity. Two cohorts of OLP patients resident in two different regions of southern Italy (Campania and Sicily;n = 859) were evaluated for HCV infection status and categorized into five age classes to respective region-matched controls. No significant difference was found between OLP patients and the general population in this area, when data were corrected by the age-stratified prevalence of HCV. Therefore, the age-specific prevalence of HCV infection in OLP patients shows a close trend of direct association with increasing age, without significant differences with the general population of each geographical area. An aetiological link between OLP and HCV cannot be inferred solely by epidemiological data. [ABSTRACT FROM AUTHOR]

Background. We compared acute hepatitis E (AH-E) and acute hepatitis A (AH-A) to investigate the epidemiology, clinical features, and prognosis of AH-E caused by an indigenous hepatitis E virus (HEV) in Japan. Methods. We enrolled 58 patients diagnosed with AH-A or AH-E (32 men and 26 women; age, 20–72 years) from December 1997 to October 2002. Phylogenetic analysis of the partial 412-nucleotide sequence of open reading frame (ORF) 2 was performed in patients with AH-E. Results. Regarding the geographic distribution of the HEV genotype, genotype III was principally distributed in Honshu Island, and genotype IV in Hokkaido Island (P = 0.0034). The phylogenetic analysis of the ORF2 region revealed that there were significant geographic differences in the distribution of the HEV strains in Japan, with some strains being widespread and some, localized. In comparison with AH-A patients, those with AH-E were older (56.1 ± 10.6 vs 45.9 ± 10.8 years; P = 0.0017). The proportion of males among patients with AH-E was significantly higher (P = 0.0001). Pyrexia was often observed in AH-A, and malaise in AH-E. Laboratory data indicate that AH-E induces a weak immunological reaction, whereas jaundice appears earlier in AH-E than in AH-A. One patient with AH-E died of acute hepatic failure, but none of those with AH-A died during the study period. Conclusions. Our results suggest that there are geographical differences between HEV strains in Japan, and that AH-E is more common in males and older patients than AH-A. Laboratory data indicate a weak immunological reaction and early appearance of jaundice in AH-E. [ABSTRACT FROM AUTHOR]

Recent studies indicate that hepatitis E virus (HEV) infection occurs not only in developing countries but also in industrialized nations. However, the characteristics of domestic infections of hepatitis E in Japan are not fully understood. We analyzed serum samples from 34 patients who were seen at a city hospital in Sendai, Japan, between January 1997 and December 2002, and who had been given the diagnosis of sporadic acute hepatitis of non-A, non-B, non-C etiology. Among these 34 patients, 3 (9%; all men; aged 54, 59, and 61 years) were positive for both IgG and IgM anti-HEV antibodies and for HEV RNA. The HEV isolates (HE-JAS1 and HE-JAS3) obtained from case 1 and case 3, respectively, segregated into genotype III; they had the highest nucleotide sequence identity, of 99.5% and 99.0%, with HE-JA7 and HE-JA8, respectively, both of which had been isolated in Iwate, a neighboring prefecture of Sendai. In contrast, the remaining HEV isolate (HE-JAS2), obtained from case 2, segregated into genotype IV; it had the highest nucleotide sequence identity, of 99.8% and 99.3%, with JKK-Sap and HE-JA3, respectively, both of which had been isolated in Hokkaido, Japan, although case 2 had never been to Hokkaido. Our three patients with hepatitis E had not traveled abroad in the preceding 1 year, had had no contact with pigs, and no history of blood transfusion. These results indicate that HEV should be considered as an etiological agent of acute hepatitis of non-A, non-B, non-C etiology in Japan. The risk factor(s) for acquiring domestic HEV infection in Japan needs to be clarified in future studies. [ABSTRACT FROM AUTHOR]

Sporadic cases of hepatitis E have been reported in industrialized countries, including Japan. The source of hepatitis E virus (HEV) in these patients is unknown, although zoonotic transmission has been suggested. To investigate whether or not rodents might be a reservoir of HEV, we conducted an epidemiological survey for the antibody to a recombinant capsid protein of HEV using serum samples from wild rodents in Japan. One hundred and fourteen of 362 (31.5%) Norway rats (Rattus norvegicus) and 12 of 90 (13.3%) black rats (Rattus rattus) were positive for anti-HEV IgG. In contrast, all of the sera from 55 mice were negative for anti-HEV IgG. The rate of antibody positivity increased with weight among Norway rats. Seropositive rats were found in all five districts surveyed in this study, but the prevalence of anti-HEV IgG in wild rats differed among these prefectures. Despite the fact that Japan is a non-endemic country of hepatitis E, widespread infection of HEV was observed among wild rats in Japan. Our results suggested that HEV or a closely related virus is circulating among wild rats in Japan. [Copyright &y& Elsevier]

We encountered a patient with sporadic acute hepatitis E who had not traveled to areas endemic for hepatitis E virus (HEV) infection and may have been infected in Japan. The patient was a 47-year-old male who had no history of blood transfusion or contact with travelers to hepatitis E-endemic regions or unspecified individuals. The disease presented with general malaise, fever, and brown urine as chief complaints in April 2002. Various hepatitis virus markers were negative, but IgM class antibodies to hepatitis E virus (anti-HEV) and HEV RNA were positive, and the patient was diagnosed with acute hepatitis E. The entire nucleotide sequence (7240 bases) of HEV (HE-JK4) isolated from this patient was determined and compared with known HEV strains. HE-JK4 belonged to genotype IV and exhibited higher similarities to genotype IV HEV strains previously isolated in Japan than to those isolated in China, Taiwan, and Vietnam. The patient''s family members living with him were negative for anti-HEV IgG and IgM, but their pet cat was anti-HEV IgG-positive. This finding suggests a potential route of infection of sporadic cases of hepatitis E in Japan. Since the presence of HEV indigenous to Japan is predicted, HEV infection should be considered in the diagnosis of acute hepatitis of unknown cause, even for patients who have not traveled abroad. [Copyright &y& Elsevier]

Objective: Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small. Methods: We analyzed 234 chronically HBV-infected Japanese patients who were treated with lamivudine for more than 12 months. They comprised patients with HBV genotype A (n = 8), genotype B (n = 21), genotype C (n = 203) and other HBV genotypes (n = 2). Results: In most patients, lamivudine resulted in normalization of alanine transaminase (ALT) levels at 6 and 12 months, and suppression of serum HBV DNA to undetectable levels by the branched chain DNA probe assay (bDNA). Rates of ALT normalization and non-detection of HBV DNA were higher among patients with genotype B than genotype C disease. The proportions of patients who achieved HBeAg loss were 27, 42 and 45% after 6 months, 1 year and 2 years, respectively. The emergence of mutations was not different among genotypes A, B and C by the Kaplan-Meier method. Multivariate analyses identified high HBV DNA level (bDNA ≥ 100 MEq/ml) as an independent factor associated with emergence of the YMDD motif mutation in all patients. Among patients with genotype C disease, which is the predominant HBV genotype in Japan, multivariate analysis also identified high HBV DNA level and HBeAg positivity as factors associated with emergence of resistance. Conclusion: Patients exhibiting these factors at the commencement of lamivudine treatment must be monitored carefully at regular intervals for emergence of viral resistance. [ABSTRACT FROM AUTHOR]

AbstractObjectives: The aims of this study were to determine the hepatitis B virus (HBV) genotypes in hepatitis delta virus (HDV) RNA-positive patients and to characterize the HBV nucleotide sequences that may be found on a distant island of Japan. Methods: This study included three patients with chronic hepatitis who were positive for hepatitis B surface antigen (enzyme-linked immunosorbent assay; ELISA), HDV antibody (ELISA) and HDV RNA by polymerase chain reaction (PCR). The HBV genotype was determined by nested PCR using type-specific primers. The first-round PCR products from two patients were sequenced, followed by an investigation of nucleotide homology. Results: Viruses from all three patients in this study were classified as HBV genotype B. Comparison with HBV isolates from geographically neighboring regions revealed that the two HBV isolates had 97.9–98.6% identity at the nucleotide level to a Chinese isolate, 98.3–98.6% identity to the Okinawa isolate and 98.6–98.8% identity to a Japanese isolate of genotype B. On phylogenetic analysis, the HBV isolates from the two patients were classified as HBV genotype B. The HBV isolates of cases 1 and 3 clustered in the same group as isolates from the Chinese mainland and Japanese mainland, which are geographically near Miyako Island. Conclusion: The HBV isolates coinfected with HDV found on Miyako Island were of genotype B. The PCR method based on genotype-specific primers was useful in determining HBV genotypes.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In Japan, hepatitis C virus (HCV) is the single most frequent cause of hepatocellular carcinoma (HCC), resulting in yearly deaths of over 30,000. Although the mechanism of how HCV induces HCC is not clear, persistent HCV infection and necro-inflammatory changes in chronic hepatitis C accelerate the development of liver cirrhosis and can eventuate in HCC. Hence, means of eradicating HCV as well as suppressing inflammation in the liver, even if patients stay infected with HCV, would decrease the incidence of HCC with chronic hepatitis C. For more than 40 years, a preparation of glycyrrhizin [Stronger Neo-Minophagen C (SNMC)] has been used for the treatment of 'allergic' hepatitis in Japan. In 1977, intravenous injection with SNMC was started in patients with chronic hepatitis or liver cirrhosis, most of whom have turned out to be infected with hepatitis viruses. In a multicenter double-blind study, alanine aminotransferase (ALT) levels decreased in the patients who received 40 ml/day of SNMC for 4 weeks at a rate significantly higher (p < 0.001) than controls receiving placebo. Furthermore, SNMC 100 ml/day for 8 weeks improved liver histology in 40 patients with chronic hepatitis, in correlation with improved ALT levels in serum. Liver cirrhosis occurred less frequently in 178 patients on long-term SNMC than in 100 controls (28 vs. 40% at year 13, p < 0.002). Finally, HCC developed less frequently in the 84 patients on long-term SNMC than in the 109 controls (13 vs. 25% at year 15, p < 0.002). Combined, these results indicate that a long-term treatment with SNMC prevents the development of HCC in the patients with chronic hepatitis. SNMC is particularly helpful in the patients with chronic hepatitis C who fail to respond to interferon and in those who cannot be treated with it for various reasons. [ABSTRACT FROM AUTHOR]

AbstractBackground: Tumour immunity does not seem to be induced effectively in tumour-bearing hosts, including in patients with hepatocellular carcinoma (HCC). One possible reason is that function of dendritic cells (DC) is decreased in such hosts. Methods: We evaluated T cell stimulatory activity and interleukin (IL)-12 production of DC and interferon (IFN)-γ and IL-10 production of T cells of peripheral blood from 12 control individuals and 21 patients with chronic hepatitis C virus (HCV) infection (six with chronic hepatitis (CH), eight with liver cirrhosis (LC) and 13 with HCC). Five hepatitis B virus (HBV)-infected patients with HCC were included as a disease control group. The DC were prepared by the culture of T cell-depleted populations of peripheral blood mononuclear cells in the presence of granulocyte-macrophage colony stimulating factor and IL-4 for a total of 11–12 days. The cytokine levels were assayed by ELISA. To test the stimulatory function of DC in T cell proliferation, mytomycin C-treated DC were cultured with allogeneic T cells from a control. Results: When the T cell-stimulatory activity of DC was expressed as stimulation index value of [3H]-thymidine incorporation of T cells, the values were lower in HCV-infected HCC (2.6 ± 1.8, P < 0.01) than in controls (5.5 ± 2.0) and CH (5.0 ± 1.3). Staphylococcus aureus Cowan 1-induced IL-12 production of DC was decreased in HCV-infected HCC (P < 0.001, P < 0.01 and P < 0.05, respectively) compared with controls, CH and LC, while similar amounts of IL-10 were produced in patients and controls. Interleukin-10 and IFN-γ production of T cells in response to anti-CD3 antibody or IL-12 were equivalent between patient groups and controls, respectively. Similarly decreased DC function and normal T cell response were observed in HBV-infected HCC patients. Conclusions: These findings suggest that the depressed function of DC is associated with pathogenesis of HCC with HBV or HCV infection. [ABSTRACT FROM AUTHOR]