Basic assessment on adding platelet measurement to legal health checkup in Japan: A cross-sectional and 20-year longitudinal study.

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.

Significance of Fib4 index as an indicator of alcoholic hepatotoxicity in health examinations among Japanese male workers: a cross-sectional and retrospectively longitudinal study.

BACKGROUND: Fib4 index (Fib4) is clinically used as a noninvasive marker of liver fibrosis. In this study, we aimed to preliminarily investigate whether Fib4 can be used to detect individuals who need assessment for alcoholic liver disease (ALD) in the general population by clarifying the detailed association of Fib4 with alcohol consumption and gamma-glutamyl transferase (GGT) among male workers. METHODS: We analyzed data sets on the comprehensive medical examinations of male workers as cross-sectional and retrospectively longitudinal studies. We enrolled 10 782 males (mean age: 52.2 ± 10.2 years) in FY2019 and 7845 males (mean follow-up: 12.6 ± 6.7 years) who could be consecutively followed up for 20 years from FY2000 to FY2019. Data were evaluated using logistic regression and COX proportional analysis. RESULTS: In the cross-sectional setting, the rate of Fib4 ≥ 2.67 in heavy drinkers (≥ 40 g of ethanol/day) was increased dose dependently in those over 65 years old, and that of body mass index ≥ 30 kg/m2 was increased in those over 60 years old, but not in those with fatty liver. The odds ratio (OR) (95% confidence interval [CI]) for heavy drinking was 4.30 (95% CI = 1.90-9.72), and GGT ≥ 200 IU/L was considerably high (OR = 29.05 [95% CI = 17.03-49.56]). In the longitudinal setting, heavy drinkers and those with GGT ≥ 200 IU/L at 10 years after the baseline showed an increased risk for Fib4 ≥ 2.67 (hazard ratio = 2.17 [95% CI = 1.58-2.98] and 7.65 [95% CI 5.26-11.12], respectively). CONCLUSIONS: The development of Fib4 ≥ 2.67 after 10 years was associated with heavy alcohol drinking and GGT level ≥ 200 IU/L. Therefore, Fib4 combined with GGT could indicate high risk of ALD. However, clinical examinations and course observations are essentially needed.

Development of performance indicators for hepatitis countermeasures as a tool for the assessment and promotion of liver cancer prevention in Japan.

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.

Occupational class and risk of hepatitis B and C viral infections: A case-control study-based data from a nationwide hospital group in Japan.

BACKGROUND: Occupational class, a proxy for socio-economic status, is a known factor for health disparities. However, no study has reported the association between occupational class and the risk of viral hepatitis B and C (HBV/HCV) infections. We investigated the effects of occupational class on the prevalence of HBV/HCV infections. METHODS: This is an unmatched hospital-based case-control study that included 12,101 patients who were diagnosed with HBV infection (ICD-10, B16.0, B16.1, B16.2, B16.9, B17.0, B18.0, B18.1) or HCV infection (ICD-10, B17.1, B18.2) and 698,168 controls (those with non-HBV/HCV-related diseases) aged ≥ 20 years who were initially hospitalized between 2005 and 2019. Patients were categorized according to occupational class (blue-collar, service, professional, and manager) and industrial sector (blue-collar, service, and white-collar). Managers in the blue-collar industry were set as the reference group, and the odds ratios (ORs) for the risk of HBV and HCV infections were calculated. RESULTS: Occupational class was significantly associated with only HCV infection risk. Professionals in all industrial sectors showed the lowest risk for HCV (OR (95% confidence intervals [CIs]) = 0.69 [0.58-0.82] in the blue-collar industry, 0.52 [0.38-0.73] in the service industry, and 0.60 [0.52-0.70] in the white-collar industry). Further, after adjusting for sex, age, and region of admitting hospital, all occupational classes in the white-collar industry showed lower risks of HCV than those in the other industries (ORs= 0.58 [0.47-0.71] in blue-collar workers, 0.74 [0.64-0.84] in service workers, 0.60 [0.52-0.70] in professionals, and 0.81 [0.64-1.02] in managers in white-collar industry). CONCLUSIONS: Occupational class was closely associated with HCV infection risk only. Considering that blue-collar workers in the white-collar industry also showed a low risk, adequate measures should be taken against hepatitis, possibly because of the screening tests and cure implemented in that population.

No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy.

It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.

Calibrating Hepatitis E Virus Serological Assays Using Asymptomatic Specimens Obtained in Japan.

This study aimed to calibrate hepatitis E virus (HEV) serological assays. We optimized the previously developed in-house HEV antibody enzyme-linked immunosorbent assay (ELISA) by setting the cutoff with an in-house serological performance panel consisting of broad HEV antibody titers and subtracting nonspecific background values for anti-HEV IgM, IgA, and IgG. We also compared the assay's performance with that of commercial serological assay kits (four kits for IgM, one for IgA, and two for IgG). Although all serological assays readily detected HEV antibodies at high titers in the symptomatic hepatitis E population, considerable variations between assays were observed in the asymptomatic population. The in-house ELISA showed a higher sensitivity for HEV IgM, IgA, and IgG than the commercial kits and detected the seroconversion of HEV IgM and IgG earlier when testing a commercially available HEV seroconversion panel. The low sensitivity of the commercial kits was due to the high setting of the original cutoff, which was demonstrated by receiver operating characteristic analysis. However, the corrected cutoff value reduced assay specificity. Background subtraction is essential to achieve high specificity because the in-house ELISA without background subtraction reduced its specificity. These results indicate that asymptomatic specimens and background subtraction contribute to the optimization of HEV serological assays. IMPORTANCE Accurate diagnosis of hepatitis E virus (HEV) infection is essential for public health surveillance and for preventing HEV-contaminated blood transfusion. Anti-HEV IgM or IgA is used as a reliable marker of recent HEV infection. However, considerable variability in the sensitivity and specificity of HEV antibody detection is observed among several commercially available assay kits. In addition, none of the HEV antibody detection methods have been approved by the U.S. Food and Drug Administration (FDA). Here, we show that the in-house enzyme-linked immunosorbent assay (ELISA) could detect HEV IgM and IgA more sensitively than commercial kits in the asymptomatic population. We also suggest that the assay performance of commercial kits might be improved by optimizing the cutoff and reducing nonspecific background noise. A sensitive serological (IgM or IgA) assay in addition to HEV RNA testing will contribute to accurate diagnosis of acute HEV infection because HEV RNA-positive duration is relatively short.

O-glycosylated HBsAg peptide can induce specific antibody neutralizing HBV infection.

BACKGROUND: Hepatitis B virus (HBV), which causes hepatitis, liver cirrhosis, and hepatocellular carcinoma, is a global human health problem. HBV contains three envelope proteins, S-, M-, and L-hepatitis B surface antigen (HBsAg). We recently found that O-glycosylated M-HBsAg, reactive with jacalin lectin, is one of the primary components of HBV DNA-containing virus particles. Thus, we aimed to analyze and target the glycosylation of HBsAg. METHODS: HBsAg prepared from the serum of Japanese patients with HBV were analyzed using mass spectrometry. The glycopeptide modified with O-glycan was generated and used for immunization. The specificity of the generated antibody and the HBV infection inhibition activity was examined. RESULTS: Mass spectrometry analysis revealed that T37 and/or T38 on M-HBsAg of genotype C were modulated by ±NeuAc(α2,3)Gal(ß1,3)GalNAc. Chemically and enzymatically synthesized O-glycosylated peptide (Glyco-PS2) induced antibodies that recognize mainly PreS2 in M-HBsAg not in L-HBsAg, whereas the non-glycosylated peptide (PS2) induced antisera recognizing L-HBsAg but not O-glycosylated M-HBsAg. The removal of O-glycan from M-HBsAg partly decreased the reactivity of the Glyco-PS2 antibody, suggesting that peptide part was also recognized by the antibody. The antibody further demonstrated the inhibition of HBV infection in human hepatic cells in vitro. CONCLUSIONS: Glycosylation of HBsAg occurs differently in different HBsAgs in a site-specific manner. The new Glyco-PS2 antibody, recognizing O-glycosylated M-HBsAg of genotype C, could inhibit HBV infection. GENERAL SIGNIFICANCE: The detailed analysis of HBsAg identified different glycosylations of HBV surface. The glycosylated peptide based on mass spectrometry analysis showed higher potential to induce functional antibody against HBV.

Testing, diagnosis of viral hepatitis, and the follow-up policy in Japan.

Viral hepatitis is one of the major infectious diseases in Japan and causes liver cirrhosis and liver cancer. Therefore, screening for hepatitis viruses was started in 2002, based on the geriatric health care program. The screening plan has now been transferred to the Health Promotion Project and it is estimated that more than half of the population has been tested for hepatitis viruses. The Basic Act on Hepatitis Measures was enacted in 2009 and the Basic Guidelines for Promotion of Control Measures for hepatitis was issued in 2011. It reported that there were about 770,000 positive people who were unaware that they were infected, and about 0.5 to 1.2 million positive people who knew they were infected but did not continue to receive medical examinations. Ten years have passed since that report and it is estimated that the number of hepatitis virus-positive individuals who need medical examination/treatment is decreasing. Therefore, in order to eradicate viral hepatitis, it is essential to identify areas and age groups in which hepatitis virus testing is inadequate, to encourage people to undergo testing and to promptly send positive patients to hepatologists for continued medical care. This review describes the current status and challenges of hepatitis virus testing measures in Japan, led by the Ministry of Health, Labour and Welfare, and the promotion of visits to medical institutions by positive patients.

Applicability of APRI and FIB-4 as a transition indicator of liver fibrosis in patients with chronic viral hepatitis.

BACKGROUND AND AIMS: The usefulness of APRI or FIB-4 is well established as a non-invasive liver fibrosis marker at a point of diagnosis in patients with chronic liver disease. However, their applicability for the monitoring of progression of liver fibrosis over time is yet to be determined. We aimed to clarify the feasibility of APRI and FIB-4 for the longitudinal evaluation of liver fibrosis in patients with chronic hepatitis B and C. METHODS: This is a multi-center retrospective and prospective cohort study, enrolling 1029 patients with HCV and 384 patients with HBV who were histologically diagnosed by liver biopsy. The observation period of retrospective and prospective study was 14 and 12 years, respectively. The APRI and FIB-4 were traced back in cases of histologically diagnosed cirrhosis, and those were prospectively analyzed after biopsy in cases diagnosed as F3 of METAVIR score, respectively. RESULTS: The averaged APRI and FIB-4 exhibited time-dependent increase in the retrospective study of hepatitis C patients (increase by 0.09/year in APRI and 0.29/year in FIB-4). In the prospective study of untreated hepatitis C patients, such increases were 0.14/year in APRI and 0.40/year in FIB-4, respectively. Neither the average of APRI nor FIB-4 showed a specific tendency with hepatitis B patients and treatment-experienced hepatitis C patients. CONCLUSION: The APRI and FIB-4 may serve as a transition indicator of liver fibrosis in anti-viral treatment-naïve patients with chronic hepatitis C.

Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients.

BACKGROUND: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. METHODS: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). RESULTS: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. CONCLUSIONS: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.

Establishing Efficient Systems through Electronic Medical Records to Promote Intra-hospital Referrals of Hepatitis Virus Carriers to Hepatology Specialists: A Multicenter Questionnaire-based Survey of 1,281 Healthcare Professionals.

Objective Persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causative factors of hepatic cirrhosis and hepatocellular carcinoma. However, the development of antiviral treatment has enabled their suppression. Therefore, the early detection and treatment of these infections are important. The objective of this study was to assess the level of awareness among healthcare professionals about hepatitis virus infection and electronic medical records alert system. Methods We surveyed healthcare professionals from 10 institutions with electronic medical records alert systems. All participants attended a lecture about the reactivation risk due to HBV infections, the most recent antiviral treatment for HCV infections, and the electronic medical records alert system. They participated in a questionnaire-based survey about their awareness of these infections, current status of intra-hospital referral, need for intra-hospital referrals before and after the lecture, and reasons for non-referral of patients to specialists. Results Responses were received from 1,281 healthcare professionals. Physicians and pharmacists had a high level of awareness about HBV and HCV. Among physicians, the level of awareness of those in the surgical field and other fields was significantly lower than that of the professionals in the internal medicine field. The awareness of the need to refer patients to hepatologists increased from 84.7-85.4% before to 93.0% after the lecture. The most frequent reasons for not referring patients previously were "I had no knowledge and/or interest" (28.1% of responses) and "All I did was explain the results orally" (24.2%). Conclusion More widespread education of healthcare personnel is important to increase the number of individuals receiving appropriate treatment from specialist physicians.

Increasing hepatitis virus screening uptake at worksites in Japan using nudge theory and full subsidies.

BACKGROUND: Despite the importance of hepatitis screening for decreasing liver cancer mortality, screening rates remain low in Japan. Previous studies show that full subsidies increase screening uptake, but full subsidies are costly and difficult to implement in low-resource settings. Alternatively, applying nudge theory to the message design could increase screening at lower costs. This study examined the effects of both methods in increasing hepatitis virus screening rates at worksites. METHODS: 1496 employees from a Japanese transportation company received client reminders for an optional hepatitis virus screening before their general health checkups. Groups A and B received a client reminder designed based on the principles of "Easy" and "Attractive," while the control group received a client reminder not developed using nudge theory. Additionally, hepatitis virus screening was offered to the control group and group A for a co-payment of JPY 612, but was fully subsidized for group B. The hepatitis virus screening rates among the groups were compared using a Chi-square test with Bonferroni correction, and the risk ratios of group A and group B to the control group were also calculated. To adjust for unobservable heterogeneity per cluster, the regression analysis was performed using generalized linear mixed models. RESULTS: The screening rate was 21.2%, 37.1%, and 86.3% for the control group, group A, and group B, respectively. And the risk ratio for group A was 1.75 (95% confidence interval [CI] 1.45-2.12) and that of group B was 4.08 (95% CI 3.44-4.83). The parameters of group A and group B also were significant when estimated using generalized linear mixed models. However, the cost-effectiveness (incremental cost-effectiveness ratio (ICER)) of the nudge-based reminder with the full subsidies was lower than that of only the nudge-based reminder. CONCLUSIONS: While fully subsidized screening led to the highest hepatitis screening rates, modifying client reminders using nudge theory significantly increased hepatitis screening uptake at lower costs per person.

A nationwide cross-sectional survey on hepatitis B and C screening among workers in Japan.

In Japan, there is no publicly funded screening for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections (using HBs antigen and HCV antibody, respectively) among workers, and workplace health programmes play a crucial role in reducing viral hepatitis-related deaths. The national number of hepatitis screening tests conducted in the workplace is unknown. To provide baseline data for policy formulation, we conducted a nationwide survey to estimate these parameters using data from approximately 10.5 million workers (6.8 million men and 3.8 million women) who underwent mandatory health examinations in their workplaces between April 2016 and March 2017. Among these workers, 494,303 (5.23%, 95% confidence interval [CI] 5.22%-5.24%) and 313, 193 (3.82%, 95% CI 3.81%-3.84%) were screened for HBV and HCV, respectively. Among those who were screened, 0.28% (95% CI 0.27-0.30%) and 0.35% (95% CI 0.33-0.37%) tested positive for HBs antigen and HCV antibody, respectively. According to the age-specific prevalence from the survey an estimated 0.30 and 0.14 million workers in Japan require treatment for HBV and HCV, respectively. To reduce viral hepatitis-related deaths by efficiently identifying workers who need treatment and promoting access to treatment, one-time hepatitis screening of all workers should be considered.

Nationwide survey on activities of regional core centers for the management of liver disease in Japan: Cumulative analyses by the Hepatitis Information Center 2009-2017.

AIM: Regional core centers for the management of liver disease, which are located in every prefecture in Japan, not only take the lead in hepatitis care in their respective regions, but also serve a wide range of other functions, such as education, promotion of hepatitis testing, treatment, and research. METHOD: Since fiscal year 2010, the Hepatitis Information Center has conducted surveys of regional core centers throughout Japan regarding information about their facilities, programs for patient support, training, and education of medical personnel. RESULTS: By compiling and analyzing the results of these surveys, we have elucidated the status of regional core centers and the issues they currently have. We found that regional core centers have come to play widely varied roles in hepatitis treatment and have expanded their programs. These surveys also suggest that uniform accessibility of hepatitis treatment has been implemented throughout Japan. CONCLUSION: To continue serving their diverse roles, regional core centers require further development of hepatitis care networks that include specialized institutions, primary care physicians, and local and central governments; as well as collaboration with other professions and groups.

High serum interleukin-34 level is a predictor of poor prognosis in patients with non-viral hepatocellular carcinoma.

AIMS: We aimed to investigate the impact of interleukin (IL)-34 and YKL-40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non-viral hepatocellular carcinoma (HCC). METHODS: We enrolled 159 non-viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL-34 and YKL-40 levels were quantified by enzyme-linked immunosorbent assay. Patients were stratified by the median level of serum IL-34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL-34 and YKL-40 on the prognosis of non-viral HCC patients. RESULTS: Interleukin-34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13-1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37-1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25-1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL-34 group than in the low IL-34 group (5-year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL-34 was the third-highest ranking factor, following tumor size and number. In a stratification analysis, serum α-fetoprotein level and Fibrosis-4 index were independent positive risk factors for high serum IL-34 level. YKL-40 was not associated with prognosis in either the multivariate or random forest analysis. CONCLUSION: Interleukin-34 was an independent factor for survival of non-viral HCC patients. Interleukin-34 might be associated with prognosis through tumor and hepatic fibrosis factors.

Efficient and practical dissemination of information on viral hepatitis in Japan: an effort by the Hepatitis Information Center, National Center for Global Health and Medicine.

One of the important missions of the Hepatitis Information Center is to disseminate information regarding liver disease. The Hepatitis Information Center, National Center for Global Health and Medicine (NCGM) has been endeavoring to ensure that reliable and up-to-date information on liver disease is accessible to all people, regardless of age, disability, and background. Described here are several initiatives with regard to the dissemination of information about liver disease including: i) Education tool for youth, ii) Conversion of materials on liver diseases into audio format for the visually impaired, and iii) Hepatic Disease Medical Navigation System (Hepatic Navi). Hepatic Navi is a web-based search tool that informs users of the location and other information concerning medical centers where people can be tested for the hepatitis virus for free or at reduced cost. Hepatic Navi consolidates data from 47 prefectures into one database. The system depicts data via an interface that can be accessed anywhere with a PC, tablet, smart phone, or mobile phone. As a result, it has become possible for anyone from anywhere to access information on hepatitis virus testing. By using Hepatic Navi, it is anticipated that general people in need feel free to access to the testing and further treatment for virus hepatitis.

Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients.

BACKGROUND: The clearance of hepatitis B surface antigen (HBsAg) loss, defined as functional cure, is a clinical target in patients with chronic hepatitis B (CH). To understand the immune responses underlying functional cure, we evaluated cytokine and chemokine expression profiles from patients with resolving and nonresolving acute hepatitis B (AH). METHODS: We cross-sectionally evaluated 41 chemokines and cytokines at the peak of hepatitis in the sera from 41 self-limited AH patients who achieved HBsAg seroconversion, 8 AH patients who failed to clear HBsAg within 1 year after the diagnosis, 8 CH patients with hepatic flare, and 14 healthy volunteers. We longitudinally examined 41 chemokines and cytokines in the sera from 4 self-limited AH patients, 3 chimpanzees inoculated with hepatitis B virus (HBV), and 2 CH patients treated with nucleotide analogs and PEG-IFN-α, one resulting in functional cure. RESULTS: In AH patients and HBV-inoculated chimpanzees with HBsAg loss, CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 were elevated at hepatitis with subsequent decline of HBsAg. Interestingly, IL-21 elevation was observed only in resolving AH patients but not in nonresolvers. CXCL13 and IL-21 elevation was not observed in CH patients who failed to attain HBsAg loss, even at hepatic flare. A concomitant increase of CXCL13 and IL-21 was significant in CH patients who attained HBsAg seroconversion with a sequential therapy. CONCLUSION: Elevation of serum CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 might be a hallmark of functional cure of AH or CH patients.

Highly Sensitive Glycan Profiling of Hepatitis B Viral Particles and a Simple Method for Dane Particle Enrichment.

Hepatitis B virus (HBV) is a double-stranded DNA virus composed of three types of viral particles. The virions are called Dane particles and the others are noninfectious subviral particles (SVPs). In blood, SVPs are detected in abundance, about 1000-10000 fold higher than Dane particles. Dane particles are hazardous because of their strong infectivity, unlike SVPs. Dane particles are covered with an envelope of glycoprotein called HBV surface antigen (HBsAg). HBsAg glycosylation is involved in viral particle formation and secretion. In this study, we established a novel and highly sensitive method for viral glycan profiling of HBsAg using small aliquots of patient serum. Our lectin microarray system could sensitively profile the glycans exposed on HBV while retaining the intact viral particle structure under nonreducing conditions. Several typical lectins were chosen from the lectin microarray results. Specifically, jacalin, which recognizes O-glycan, showed specific and strong reactivity to the M-HBsAg required for Dane particle secretion. Employing the lectin-fractionation method using jacalin, HBV particles were fractionated into jacalin-bound and unbound fractions from patient serum. We measured HBsAg titer and viral DNA load in each fraction using clinical tests. Interestingly, the jacalin-bound fraction contained a major fraction of the HBV viral DNA load. Thus, in this study we have presented a glycan profiling method for HBsAg on the intact HBV particle and an easy and simple method to enrich Dane particles from patient serum by jacalin fractionation.

Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease.

Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68).

Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients.

This study examines the role of M2BPGi, a novel seromarker for chronic hepatitis, in predicting hepatocellular carcinoma (HCC) among untreated chronic hepatitis B (CHB) patients. In this nested case-control study, 1070 samples were assayed for M2BPGi, including 357 samples from HCC cases, and 713 samples from non-HCC controls, collected at various times throughout follow-up. HCC case samples were stratified according to years prior to diagnosis. Associations between M2BPGi and HCC were examined with multivariate logistic regression. M2BPGi, α-fetoprotein (AFP), and hepatitis B surface antigen (HBsAg) levels were significant independent short-term predictors of HCC, while M2BPGi was insignificant in long-term analyses. Compared to M2BPGi levels <1.0 cut-off index (COI), those with levels ≥2.0 COI had multivariate odds ratios (95% CI) for HCC of 7.40 (2.40-22.78), 6.46 (2.58-16.18), and 2.24 (0.97-5.15), respectively, for prediction of HCC within 1-2, 2-5, and ≥5 years. Higher proportions of individuals had M2BPGi levels ≥2.0 COI in samples closer to HCC diagnosis. Areas under receiver operating characteristic curves for models with M2BPGi, AFP, and HBsAg levels predicting HCC within 1-2, 2-5, and >5 years were 0.84, 0.81, and 0.75. M2BPGi is a strong and independent short-term predictor of HCC in CHB patients.