Allograft liver failure awaiting liver transplantation in Japan.

BACKGROUND: Following liver transplantation (LT), allograft liver failure can be developed by various causes and requires re-LT. Hence, this study aimed to clarify the characteristics and prognostic factors of patients with allograft liver failure awaiting deceased donor LT (DDLT) in Japan. METHODS: Of the 2686 DDLT candidates in Japan between 2007 and 2016, 192 adult patients listed for re-LT were retrospectively enrolled in this study. Factors associated with waitlist mortality were assessed using the Cox proportional hazards model. The transplant-free survival probabilities were evaluated using the Kaplan-Meier analysis and log-rank test. RESULTS: The median period from the previous LT to listing for re-LT was 1548 days (range, 4-8449 days). Primary sclerosing cholangitis (PSC), which was a primary indication, showed a higher listing probability for re-LT as compared with other primary etiologies. Recurrent liver disease was a leading cause of allograft failure and was more frequently observed in the primary indication of hepatitis C virus (HCV) infection and PSC in contrast with other etiologies. Multivariate analysis identified the following independent risk factors associated with waitlist mortality: age, Child-Turcotte-Pugh (CTP) score, mode for end-stage liver disease (MELD) score, alanine aminotransferase (ALT), and causes of allograft failure. CONCLUSIONS: Recurrent HCV and PSC were major causes of allograft liver failure in Japan. In addition to CTP and MELD scores, either serum ALT levels or causes of allograft failure should be considered as graft liver allocation measures.

Serum O-glycosylated hepatitis B surface antigen levels in patients with chronic hepatitis B during nucleos(t)ide analog therapy.

BACKGROUND: Serum hepatitis B surface antigen (HBsAg) is a component of both hepatitis B virus (HBV) virions and non-infectious subviral particles (SVPs). Recently, O-glycosylation of the PreS2 domain of middle HBsAg protein has been identified as a distinct characteristic of genotype C HBV virions versus SVPs. This study aimed to evaluate serum O-glycosylated HBsAg levels in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogs (NAs). METHODS: Forty-seven treatment-naïve patients with genotype C CHB were retrospectively enrolled. Serum O-glycosylated HBsAg levels at baseline and after 48 weeks of NA therapy were quantified by immunoassay using a monoclonal antibody against the O-glycosylated PreS2 domain of middle HBsAg, and their correlations with conventional HBV marker levels were analyzed. RESULTS: At baseline, the serum O-glycosylated HBsAg levels were significantly correlated with the HBV DNA (P = 0.004), HBsAg (P = 0.005), and hepatitis B-core related antigen (HBcrAg, P = 0.001) levels. Both HBV DNA and O-glycosylated HBsAg levels were decreased after 48 weeks of NA therapy. The significant correlation of the O-glycosylated HBsAg level with the HBsAg or HBcrAg level was lost in patients who achieved undetectable HBV DNA (HBsAg, P = 0.429; HBcrAg, P = 0.065). Immunoprecipitation assays demonstrated that HBV DNA and RNA were detected in the O-glycosylated HBsAg-binding serum fraction, and the proportion of HBV RNA increased during NA therapy (P = 0.048). CONCLUSION: Serum O-glycosylated HBsAg levels change during NA therapy and may reflect combined levels of serum HBV DNA and RNA virions. An O-glycosylated HBsAg-based immunoassay may provide a novel means to monitor viral kinetics during NA therapy.

Outcome of patients with acute liver failure awaiting liver transplantation in Japan.

AIM: To clarify the outcome and predictive factors in patients with acute liver failure (ALF) awaiting deceased donor liver transplantation (DDLT) in Japan. METHODS: Of the DDLT candidates in Japan between 2007 and 2016, 264 adult patients with ALF were retrospectively enrolled in this study. Factors associated with DDLT and waiting-list mortality were assessed using the Cox proportional hazard model. The DDLT and transplant-free survival probabilities were evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: The waiting-list registration year after the Transplant Law revision in 2010 was a significant factor associated with DDLT. The adjusted hazard ratio indicated that DDLT probability after 2010 was four times higher than that before, and the 28-day cumulative DDLT probability was more than 35%. The median survival time of the entire cohort was 40 days. Multivariate analysis identified the following three factors associated with waiting-list mortality: age, coma grade, and international normalized ratio. The transplant-free survival probabilities were significantly stratified by the number of risks, and patients with all three risks showed extremely poor short-term prognosis (median survival time = 23 days). CONCLUSIONS: The DDLT probability of ALF patients increased after the law revision in 2010; however, patients at high risk of short-term waiting-list mortality might need emergent living donor transplantation.

Multidisciplinary attentive treatment for patients with chronic disorders of consciousness following severe traumatic brain injury in the NASVA of Japan.

Primary Objective: The aim of this study was to demonstrate the clinical outcomes of long-term multidisciplinary attentive treatment (MAT) in patients with chronic disorders of consciousness (DOC) due to severe traumatic brain injury (TBI) following automotive accidents.Research Design: Five hundred and ten patients (mean age: 40.4 years) were enrolled in this retrospective study.Methods and Procedures: Patients were provided MAT for one to several years in the eight medical facilities of the National Agency for Automotive Safety and Victims' Aid (NASVA) in Japan. Clinical status for consciousness, communication, and activities of daily living were evaluated using the NASVA grading system.Outcomes and results: Following MAT, NASVA scores at discharge were significantly improved compared to those at admission in every patient subgroup including sex, age, NASVA score, and association with/without hypoxic encephalopathy at admission. Younger age, shorter interval between injury and admission, and better neurocognitive function at admission were found to be significant and independent factors for a good prognosis.Conclusions: MAT can partially improve the cognitive and physical abilities of patients with chronic DOC. From the perspective of not only restoring a patient's daily life, but also reducing the caregiver's burden, this type of treatment program warrants more public attention.

Portal Vein Thrombosis in a Patient with Hereditary Antithrombin Deficiency.

Portal vein thrombosis (PVT) has been reported in many patients with and without liver cirrhosis. The portal vein is a rare site of thrombosis, and various conditions can predispose an individual to PVT. Among those conditions, hereditary thrombophilia has been increasingly reported recently. We herein report the case of a non-cirrhotic 30-year-old man who developed acute PVT with hereditary antithrombin deficiency. Antithrombin (AT) replacement therapy was required along with heparin. Given our experience with this case, we believe that a screening test for prothrombotic disorders, such as AT deficiency, should be considered in cases of PVT.

Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial.

AIM: The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. METHODS: Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18-36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. RESULTS: In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH3 ) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. CONCLUSION: The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

Aldo-keto reductase family 1 member B10 is associated with hepatitis B virus-related hepatocellular carcinoma risk.

AIM: Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. METHODS: Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis. RESULTS: Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively (P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. CONCLUSION: Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis.

Survival in patients with Child-Pugh class C cirrhosis: Analysis of the liver transplant registry in Japan.

AIM: To clarify the survival and prognostic factors in patients with Child-Turcotte-Pugh class C (CTP-C) cirrhosis. METHODS: From all candidates for deceased donor liver transplantation in Japan between 2007 and 2015, 1014 adult patients with CTP-C cirrhosis were retrospectively enrolled in this study. The hazard ratio (HR) of factors associated with mortality was estimated by the Cox proportional hazard model. The survival probabilities were evaluated by Kaplan-Meier analysis and the log-rank test. RESULTS: Median survival time of the entire cohort was 475 days. Univariate analysis identified age, CTP, Model for End-Stage Liver Disease (MELD) score, and primary biliary cholangitis (PBC) as significant variables associated with mortality and hepatitis B virus (HBV) infection as a close-to-significant variable. Multivariate analysis revealed that age-adjusted mortality risk increased by 59% and 12% per 1 score step up in CTP and MELD scores, respectively. The HRs for HBV infection and PBC were significant after adjustment for age and CTP score, and they showed a 26% lower risk and an 83% higher risk than hepatitis C virus (HCV) infection, respectively. After adjustment for age and MELD score, the HR was also significant for HBV infection, but lost statistical significance for PBC. The survival curves were well stratified by both CTP or MELD score and revealed significant difference in both HBV infection and PBC as compared to HCV infection. CONCLUSIONS: In patients with CTP-C cirrhosis, CTP and MELD scores could well stratify the patients' survival, and HBV infection and PBC as etiologies have an impact on survival.

Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA⁺-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA⁺-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA⁺-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA⁺-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA⁺-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA⁺-M2BP level is a useful predictor for HCC development after achieving SVR.

Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication.

AIM: To clarify the association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and hepatocarcinogenesis after hepatitis C virus eradication. METHODS: In this study, we enrolled 303 chronic hepatitis C patients who had achieved sustained virological response (SVR) through interferon-based antiviral therapy. Pretreatment AKR1B10 expression in the liver was immunohistochemically assessed and quantified as a percentage of positive staining area by using image-analysis software. A multivariate Cox analysis was used to estimate the hazard ratios (HRs) of AKR1B10 expression for hepatocellular carcinoma (HCC) development after achieving SVR. The cumulative incidences of HCC development were evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: Of the 303 chronic hepatitis C patients, 153 (50.5%) showed scarce hepatic AKR1B10 expression, quantified as 0%, which was similar to the expression in control normal liver tissues. However, the remaining 150 patients (49.5%) exhibited various degrees of AKR1B10 expression in the liver, with a maximal AKR1B10 expression of 73%. During the median follow-up time of 3.6 years (range 1.0-10.0 years), 8/303 patients developed HCC. Multivariate analysis revealed that only high AKR1B10 expression (≥ 8%) was an independent risk factor for HCC development (HR = 15.4, 95%CI: 1.8-132.5, P = 0.012). The 5-year cumulative incidences of HCC development were 13.7% and 0.5% in patients with high and low AKR1B10 expression, respectively (P < 0.001). During the follow-up period after viral eradication, patients expressing high levels of AKR1B10 expressed markedly higher levels of alanine aminotransferase and α-fetoprotein than did patients exhibiting low AKR1B10 expression. CONCLUSION: Chronic hepatitis C patients expressing high levels of hepatic AKR1B10 had an increased risk of HCC development even after SVR.

Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. METHODS: Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. RESULTS: Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) =0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR=0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. CONCLUSIONS: For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible.

Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan.

BACKGROUND: Beginning in 1967, the Liver Cancer Study Group of Japan (LCSGJ) started a nationwide prospective registry of all patients with hepatocellular carcinoma (HCC) diagnosed at more than 700 institutions. To determine the effectiveness of surveillance and treatment methods longitudinally, we analyzed improvements over time in overall survival (OS) of 173,378 patients with HCC prospectively entered into the LCSGJ registry between 1978 and 2005. METHODS: All patients from more than 700 institutions throughout Japan with HCC were entered into the LCSGJ registry. Patients were grouped by years of diagnosis, with OS and 5-year OS rates being calculated. We also assessed OS and 5-year OS rates in patients who underwent resection, local ablation, transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy (HAIC) and in those with baseline serum alpha-fetoprotein (AFP) levels ≥400 ng/ml. RESULTS: The 5- and 10-year OS rates in the cohort of 173,378 patients were 37.9% and 16.5%, respectively. However, over time, the mean maximum tumor size decreased significantly, whereas 5-year OS rates and median survival time increased significantly. Similar findings were observed separately in patients who underwent resection, local ablation, TACE, and HAIC, as well as in patients with AFP levels ≥400 ng/ml. CONCLUSION: The establishment of a nationwide HCC surveillance program in Japan has contributed to longer median OS and increased OS rates in patients diagnosed with this disease. These findings suggest that the establishment of a surveillance program in other countries with patients at risk for HCC may provide significant survival benefits.

Report of the 19th follow-up survey of primary liver cancer in Japan.

The 19th Nationwide Follow-up Survey of Primary Liver Cancer in Japan comprised 20 850 primary liver cancer patients newly registered at 482 medical institutions over a period of 2 years (from 1 January 2006 to 31 December 2007). Of these, 94.7% had hepatocellular carcinoma (HCC) and 4.4% had intrahepatic cholangiocarcinoma (ICC). In addition, follow-up data were obtained regarding 34 752 patients who were registered in the previous survey. Epidemiological and clinicopathological factors, diagnosis, and treatment were examined in newly registered patients. Compared with the 18th follow-up survey, the present follow-up survey suggested an increase in the number of elderly and female patients, a reduction in the number of hepatitis B surface antigen- and anti-hepatitis C virus antibody-positive patients, and a reduction in tumor size at the time of clinical diagnosis. In terms of local ablation therapy, the number of patients receiving radiofrequency ablation therapy increased. The cumulative survival rates for newly registered patients between 1996 and 2007 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified according to background factors and treatments. The cumulative survival rates of newly registered patients between 1978 and 2007 were calculated after dividing individuals into groups according to registration date (1978-1987, 1988-1997, and 1998-2007). The data obtained from this follow-up survey will contribute to the medical management of primary liver cancer and facilitate future research.

Impact of aldo-keto reductase family 1 member B10 on the risk of hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was recently reported to be upregulated in some chronic liver diseases. However, its relevance in hepatocellular carcinoma (HCC) development is not fully assessed, especially in patients with chronic hepatitis C virus (HCV) infection. METHODS: Aldo-keto reductase family 1 member B10 expression in the liver of 550 patients with chronic HCV infection was immunohistochemically assessed and quantified. A multivariate Cox model was used to estimate the hazard ratios (HRs) of AKR1B10 expression for HCC development, and the cumulative incidence of HCC was evaluated using the Kaplan-Meier method. RESULTS: Aldo-keto reductase family 1 member B10 expression in the patients ranged from 0% to 80%. During the median follow-up of 3.2 years, 43 of 550 patients developed HCC. Multivariate analysis demonstrated that high AKR1B10 expression (≥6%) was an independent risk factor for HCC (HR, 6.43; 95% confidence interval, 2.90-14.25; P < 0.001). The 5-year cumulative incidences of HCC were 22.8% and 2.2% in patients with high and low AKR1B10 expression, respectively (P < 0.001). In subgroup analyses, the effects of high AKR1B10 expression on HCC development risk were significant over strata. In particular, HRs attributed to high AKR1B10 expression were significant in the subgroups that had been considered at a lower risk of HCC, such as in patients with younger age and mild hepatic fibrosis or those who achieved sustained virological response after interferon therapy. CONCLUSION: Various degrees of AKR1B10 upregulation in the liver were observed in patients with chronic HCV infection, and high AKR1B10 expression could be a novel predictor of HCC.

Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan.

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.

Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines).

The 3rd version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine, which was published in October 2013 in Japanese. Here, we briefly describe new or changed recommendations with a special reference to the two algorithms for surveillance, diagnosis, and treatment.

A comparison of the surgical outcomes among patients with HBV-positive, HCV-positive, and non-B non-C hepatocellular carcinoma: a nationwide study of 11,950 patients.

OBJECTIVE: To compare the prognostic factors and outcomes after hepatic resection among patients with hepatitis B virus (HBV)-positive, hepatitis C virus (HCV)-positive, and negative for hepatitis B surface antigen and hepatitis C antibody, so-called "NBNC"-hepatocellular carcinoma (HCC) using the data from a nationwide survey. BACKGROUND: The incidence of NBNC-HCC is rapidly increasing in Japan. METHODS: A total of 11,950 patients with HBV-HCC (n = 2194), HCV-HCC (n = 7018), or NBNC-HCC (n = 2738) who underwent a curative hepatic resection were enrolled in this study. The clinicopathological features were compared among the groups. The significant prognostic variables determined by univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. RESULTS: Liver function in the HCV-HCC group was significantly worse than that in the HBV-HCC and NBNC-HCC groups. The NBNC-HCC group had significantly more advanced HCC than the HCV-HCC group. The 5-year overall survival rates after hepatectomy in the HBV-HCC, HCV-HCC, and NBNC-HCC groups were 65%, 59%, and 68%, respectively. The 5-year recurrence-free survival (RFS) rates in these 3 groups were 41%, 31%, and 47%, respectively. Stratifying the RFS rates according to the TNM stage showed that the NBNC-HCC group had a significantly better prognosis than the HBV-HCC group in stages II, III, and IVA, and a significantly better prognosis than the HCV-HCC group in stages I and II. Multivariate analysis revealed a significantly better RFS rate in the NBNC-HCC group. CONCLUSIONS: The findings of this nationwide survey indicated that patients with NBNC-HCC had a significantly lower risk of HCC recurrence than those with HBV-HCC and HCV-HCC.

Presence of antibodies against self human leukocyte antigen class II molecules in autoimmune hepatitis.

Autoimmune hepatitis (AIH) can arise de novo after liver transplantation (LT) for non-autoimmune liver diseases. Considering the identical features of de novo AIH after LT and classical AIH, as well as the importance of anti-human leukocyte antigen (HLA) antibodies in graft rejection, we investigated the presence of circulating anti-HLA class II antibodies in the sera of 35 patients with AIH, 30 patients with primary biliary cirrhosis (PBC), and 30 healthy donors using fluorescent dye-impregnated beads bound to HLA molecules. We then investigated the allele specificity of the antibodies and identified the HLA alleles in each patient using DNA-based HLA typing. We also examined HLA class II expression in liver samples using immunohistochemistry. Anti-HLA class II antibodies were detected significantly more frequently in the patients with AIH (88.1%) than in the patients with PBC (33.3%) or in the healthy donors (13.3%) (both P <0.01). We confirmed that the anti-HLA class II antibodies in the AIH patients showed specificity for several HLA class II alleles, including self HLA class II alleles. Moreover, positive reactivity with anti-self HLA class II antibodies was associated with higher serum transaminase levels. In conclusion, we demonstrated, for the first time, that antibodies against self HLA class II alleles were detectable in patients with AIH. Our results suggest that an antibody-mediated immune response against HLA class II molecules on hepatocytes may be involved in the pathogenesis or acceleration of liver injury in AIH.

Imbalance between CD56+bright and CD56+dim natural killer cell subsets in the liver of patients with recurrent hepatitis C after liver transplantation.

Progressive liver fibrosis remains a major problem for patients with recurrent chronic hepatitis C(CHC) after liver transplantation (LT). However, the involvement of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in recurrent CHC after LT remains unclear.In the present study, we investigated the status of NK and NKT cells in the liver and peripheral blood obtained from 10 patients with recurrent CHC after LT (LT-C), 15 patients with CHC, and 7 normal donors for living donor LT. CD56+ NK cells were separated into two subsets: CD56+bright subset, which is identified as major NK cytokine producer, and CD56+dim subset, which has greater spontaneous cytotoxicity. We found a significant decrease in the CD56+bright subset in the liver of patients with LT-C compared to patients with CHC (P<0.01) and normal donors (P=0.03). The expression of inhibitory NK cell receptor NKG2A was significantly increased on intrahepatic CD56+bright subset in LT-C patients, and activated CD69+CD56+dim NK cell subset was significantly increased in the liver of LT-C patients. Our results suggest that a significant imbalance between CD56+bright and CD56+dim NK cell subsets in the liver may contribute to the progression of recurrent CHC after LT.