A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH AND RESULTS: Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Zinc supplementation with polaprezinc was associated with improvements in albumin, prothrombin time activity, and hemoglobin in chronic liver disease.

Zinc deficiency occurs in a variety of diseases, including chronic liver disease (CLD). We investigated the correlation between zinc levels and biochemical and hematological tests in CLD and the effect of zinc supplementation with polaprezinc on these values. The first study (Study 1) was a retrospective observational study of 490 patients with CLD not receiving zinc supplementation, with data available from September 2009 to August 2021. Univariate and multiple regression analysis showed that serum zinc levels correlated most strongly with albumin (Alb) and also significantly with prothrombin time activity (PT%) and hemoglobin (Hb). A subsequent study (Study 2) focused on patients with advanced CLD who used polaprezinc for more than 90 days between January 2005 and August 2021. Using a self-controlled design with the 6-month period prior to polaprezinc as the control period, comparisons showed that Alb (p<0.0001), PT% (p<0.0005), and Hb (p<0.01) were significantly improved in the polaprezinc-treated patients compared to the control group. In conclusion, serum zinc levels were correlated with serum Alb, Hb, and PT% in patients with CLD, and zinc supplementation with polaprezinc was associated with improvements in Alb, Hb, and PT% within at least 6 months.

Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures.

BACKGROUND & AIMS: Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. METHODS: We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/µL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/µL or more with an increase of 20,000/µL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded. RESULTS: The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/µL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/µL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/µL or more). CONCLUSION: In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients. The mechanism underlying disease progression is largely unknown. p53-binding protein 1 (53BP1) is a DNA damage response protein that rapidly localizes at the site of DNA double-strand breaks. In this study, we investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease liver tissues by immunofluorescence microscopy. A total of 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls, were studied. Our results show that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 µM) was significantly increased in nonalcoholic fatty liver disease patients compared to that in controls, both in nonalcoholic fatty liver (p < 0.01) and nonalcoholic steatohepatitis patients (p < 0.01). The number of large foci was significantly increased in the nonalcoholic steatohepatitis cases compared to that in the nonalcoholic fatty liver cases (p < 0.05) and correlated with increased stage of fibrosis. The number of large-foci-expressing hepatocytes was positively correlated with increased age (p < 0.01) and negatively correlated with serum platelet count (p < 0.05). In addition, we performed an in vitro assay using rat hepatocytes treated with the saturated free fatty acid palmitate. Treatment appeared to augment the number of abnormal foci, indicating an induction of double-strand breaks in the hepatocytes through free fatty acid treatment in a caspase-dependent manner. This study demonstrates that 53BP1-positive nuclear foci formation is associated with disease progression in nonalcoholic fatty liver disease patients. Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population.

Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03-1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12-1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.

Association of a single nucleotide polymorphism upstream of ICOS with Japanese autoimmune hepatitis type 1.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.

Hepatic flares promote rapid decline of serum hepatitis B surface antigen (HBsAg) in patients with HBsAg seroclearance: A long-term follow-up study.

AIM: Serum hepatitis B surface antigen (HBsAg) seroclearance is one of the ultimate goals of management of chronic hepatitis B. We investigated the kinetics of serum HBsAg before HBsAg seroclearance in patients with chronic hepatitis B. METHODS: We retrospectively analyzed 392 Japanese chronic hepatitis B patients who had been followed for 5 years or more between 1980 and 2000. Serum HBsAg levels were measured annually using chemiluminescent enzyme immunoassay. RESULTS: During a median follow up of 14 years, 50 patients demonstrated HBsAg seroclearance (annual incidence rate, 0.91%). Multivariate analysis with baseline characteristics revealed that HBsAg of less than 3.3 log IU/mL (hazard ratio [HR], 2.22; P = 0.008) and treatment with nucleoside/nucleotide analog (HR, 0.12; P = 0.001) were independent predictive factors for seroclearance. The median HBsAg levels at 20, 10, 5, 3 and 1 year prior to seroclearance were 3.89, 2.84, 1.84, 0.78 and -1.10 log IU/mL, respectively. The rapid decline group, comprising patients who achieved HBsAg seroclearance within 5 years after confirmed HBsAg levels of 2 log IU/mL, demonstrated: (i) high alanine aminotransferase (ALT) levels; and (ii) a low frequency of liver cirrhosis progression. A significant reduction in annual HBsAg levels was found in years marked by at least one ALT flare (ALT ≥200 IU/L) (flare [+], n = 62) than in those without (flare [-], n = 323) (0.29 vs 0.17 log IU/mL/year, P = 0.003). CONCLUSION: Hepatic flares promoted rapid declines and greater annual reductions of HBsAg levels in patients with HBsAg seroclearance.

Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients.

UNLABELLED: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P<0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age>57 years, F4, AFP>20 ng/mL, WFA+-M2BP ≥4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. CONCLUSION: WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy.

Systemic and local expression levels of TNF-like ligand 1A and its decoy receptor 3 are increased in primary biliary cirrhosis.

BACKGROUND & AIMS: Through a genome-wide association study of a Japanese population, we recently identified TNFSF15, a gene encoding TNF-like ligand 1A (TL1A), as a susceptibility gene for primary biliary cirrhosis (PBC). We investigated the clinical significance of TL1A and one of its receptors, decoy receptor 3 (DcR3), in PBC. METHODS: We analysed the systemic and local expression of TL1A and DcR3 in 110 PBC patients and 46 healthy controls using enzyme-linked immunosorbent assay, quantitative polymerase chain reaction and immunohistochemical staining. RESULTS: Serum TL1A levels were significantly increased in PBC patients at both early and late stages as compared with healthy controls, and its levels were significantly decreased in early-stage PBC patients after ursodeoxycholic acid (UDCA) treatment. TL1A was immunohistochemically localized to biliary epithelial cells, Kupffer cells, blood vessels and infiltrating mononuclear cells in the PBC liver. In addition, TL1A messenger RNA expression was increased in the PBC liver as compared with the non-diseased liver. Serum DcR3 levels were also significantly increased in PBC patients, and were significantly decreased after UDCA treatment in early-stage PBC patients. CONCLUSIONS: These results indicate that TL1A and DcR3 may play an important role in the pathogenesis of PBC.

Sequential occurrence of acute hepatitis B among members of a high school Sumo wrestling club.

A 17-year-old male was admitted to our hospital and diagnosed with acute hepatitis B. Six weeks later, a 15-year-old male was admitted with acute hepatitis B as well. They were Sumo wrestling players in the same club. A detailed survey in the club revealed that a 28-year-old male coach was a hepatitis B surface antigen carrier with high-level viremia. The consistency of hepatitis B virus (HBV) DNA in the infected players was revealed by analyzing the complete HBV genome sequences. Sumo players are more likely to get injured, including cuts and bleeding, compared with players of other sports because of the characteristic wrestling style. Several past reports have suggested that highly viremic HBV carriers have high HBV DNA titers in both their blood and other body fluids such as sweat. In our cases, percutaneous HBV transmission through the bleeding wounds was the most probable infection route. We conclude that a universal HBV immunization program should be introduced urgently in Japan, similar to those implemented in other countries worldwide.

Coexistence of familial Mediterranean fever and rheumatoid arthritis.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent febrile polyserositis and arthritis. Although accompanying seronegative spondyloarthropathy has been reported in FMF, coexistence with rheumatoid arthritis (RA) is very rare. This case report describes a Japanese female RA patient who presented with periodic fever. Genetic analysis revealed compound heterozygous mutations in exon 2 and 3 of the MEFV gene (E148Q/G304R/P369S/R408Q). The patient was successfully treated with colchicine with 3-year follow-up.

Hepatitis B virus strains of subgenotype A2 with an identical sequence spreading rapidly from the capital region to all over Japan in patients with acute hepatitis B.

OBJECTIVE: To examine recent trends of acute infection with hepatitis B virus (HBV) in Japan by nationwide surveillance and phylogenetic analyses. METHODS: During 1991 through 2009, a sentinel surveillance was conducted in 28 national hospitals in a prospective cohort study. Genotypes of HBV were determined in 547 patients with acute hepatitis B. Nucleotide sequences in the preS1/S2/S gene of genotype A and B isolates were determined for phylogenetic analyses. RESULTS: HBV genotype A was detected in 137 (25% (accompanied by genotype G in one)) patients, B in 48 (9%), C in 359 (66%), and other genotypes in the remaining three (0.5%). HBV persisted in five with genotype A including the one accompanied by genotype G; another was co-infected with HIV type 1. The genotype was A in 4.8% of patients during 1991-1996, 29.3% during 1997-2002, and 50.0% during 2003-2008 in the capital region, as against 6.5%, 8.5% and 33.1%, respectively, in other regions. Of the 114 genotype A isolates, 13 (11.4%) were subgenotype A1, and 101 (88.6%) were A2, whereas of the 43 genotype B isolates, 10 (23.3%) were subgenotype B1, 28 (65.1%) were B2, two (4.7%) were B3, and three (7.0%) were B4. Sequences of 65 (64%) isolates of A2 were identical, as were three (23%) of A1, and five (18%) of B2, but none of the B1, B3 and B4 isolates shared a sequence. CONCLUSIONS: Acute infection with HBV of genotype A, subgenotype A2 in particular, appear to be increasing, mainly through sexual contact, and spreading from the capital region to other regions in Japan nationwide. Infection persisted in 4% of the patients with genotype A, and HBV strains with an identical sequence prevailed in subgenotype A2 infections. This study indicates the need for universal vaccination of young people to prevent increases in HBV infection in Japan.

Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study).

BACKGROUND/AIMS: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. RESULTS: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. CONCLUSIONS: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.

Prediction of early HBeAg seroconversion by decreased titers of HBeAg in the serum combined with increased grades of lobular inflammation in the liver.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is an important hallmark in the natural course of chronic hepatitis B. This study was designed to predict early HBeAg seroconversion within 1 year, by not only biochemical and virological markers, but also pathological parameters in patients with chronic hepatitis B. MATERIAL/METHODS: In a retrospective cohort study, 234 patients with HBeAg were reviewed for demographic, biochemical, virological and pathological data at the time of liver biopsy. Then, the patients who accomplished HBeAg seroconversion within 1 year thereafter were compared with those who did not, for sorting out factors predictive of early HBeAg seroconversion. RESULTS: Early HBeAg seroconversion occurred in 58 (24.8%) patients. In univariate analysis, factors predictive of early HBeAg seroconversion were: alanine aminotransferase (ALT) (p=0.002), IP-10 (p=0.029), HBsAg (p=0.003), HBeAg (p<0.001), HBV DNA (p=0.001), HBcrAg (p=0.001), core-promoter mutations (p=0.040), fibrosis (p=0.033) and lobular inflammation (p=0.002). In multivariate analysis, only serum HBeAg levels <100 Paul Ehrlich Institute (PEI) U/ml and grades of lobular inflammation ≥2 were independent factors for early HBeAg seroconversion (odds ratio 8.430 [95% confidence interval 4.173-17.032], p<0.001; and 4.330 [2.009-9.331], p<0.001; respectively). CONCLUSIONS: HBeAg levels < 100 PEIU/ml combined with grades of lobular inflammation ≥2 are useful for predicting early HBeAg seroconversion. In patients without liver biopsies, high ALT levels (≥200 IU/L) can substitute for lobular inflammation (grades ≥2).

Ferritin/alanine aminotransferase ratio as a possible marker for predicting the prognosis of acute liver injury.

BACKGROUND AND AIMS: Serum levels of ferritin and heme oxygenase (HO)-1 are both markers of macrophage activation. We evaluated simple markers for predicting the prognosis of severe acute liver injury in which macrophage activation plays an important role. METHODS: Subjects comprised 114 patients with acute liver injury, admitted to the liver unit of Nagasaki Medical Center between January 2001 and September 2010. Subjects included 11 patients with fulminant hepatic failure (FHF), 82 patients with ordinary acute hepatitis (AH), and 21 patients with severe-form AH (AHS). We determined serum levels of ferritin, HO-1 and other biochemical makers, and analyzed relationships between clinical outcomes of patients and each of these parameters alone and in combination. RESULTS: Median serum ferritin levels were significantly higher in FHF (25900ng/mL) and AHS (3060ng/mL) than in AH (700ng/mL; P<0.01 each). Median HO-1 levels were also significantly higher in FHF (123ng/mL) and AHS (51ng/mL) than in AH (19ng/mL; P<0.01 each). Similarly, median ferritin/alanine aminotransferase (F/A) ratio was significantly higher in FHF (6.7) than in AHS (1.6, P<0.05) or AH (0.5, P<0.01). Among the 11 FHF patients, three recovered, seven died and one underwent liver transplantation. The ability of F/A ratio to distinguish non-survivors from survivors was analyzed using receiver operating characteristics curves. A cut-off level of 3.12 provided high sensitivity (87.5%) and specificity (81.2%). CONCLUSION: These results suggest that F/A ratio offer a quick and simple marker for predicting the prognosis of acute liver injury.

Integrated fibrosis scoring by ultrasonography predicts the occurrence of hepatocellular carcinoma in patients with chronic hepatitis C virus infection.

PURPOSE: This study was performed to elucidate whether evaluating the liver surface, edge, and texture by high-resolution ultrasonography is useful for predicting the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-associated chronic liver diseases (CLDs) METHODS: The integrated fibrosis stage (a comprehensive value of scores for liver edge, surface, and texture) of 337 patients with HCV-associated CLDs was evaluated, at entry, by ultrasonography (US), as a US score. The patients were followed up prospectively (mean observation period was 16.4 months; range 2.8-36.2 months) for the occurrence of HCC by US or helical CT at 3-month intervals. A total of 140 patients received interferon therapy, and the occurrence of HCC was compared between those with and without interferon therapy RESULTS: The annual incidence of HCC was 1.1, 5.5, and 10.2% in low, middle, and high US score groups, respectively. Univariate analysis showed that age, serum levels of total bilirubin, alpha-fetoprotein (AFP), platelet count, albumin, total cholesterol, and the US score were associated with HCC occurrence in the patients. A multivariate proportional hazard model revealed that only the middle and high US scores (p = 0.0922, hazard ratio 4.006, 95% CI 0.796-20.153 and p = 0.008, hazard ratio 7.991, 95% CI 1.721-37.10, respectively) and elevated AFP (p = 0.031, hazard ratio 2.774, CI 1.097-7.014) were independently associated with HCC occurrence. Our US scoring based on evaluation of the liver surface, edge, and texture was clearly and strongly associated with the occurrence of HCC in patients with HCV-associated CLDs, and with the higher occurrence rate of HCC in patients with higher US scores CONCLUSION: Thus, US is a good tool for evaluating the fibrosis stage of the liver, and may therefore be useful in designing an optimum follow-up interval for each patient with HCV-associated CLD.

Serum BAFF and APRIL levels in patients with PBC.

B-cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are known to be involved in the occurrence of autoimmune diseases. We assessed serum levels of these cytokines in PBC patients. Serum BAFF levels were significantly higher in PBC patients than in healthy controls (1253.9+/-741.4 vs. 722.8+/-199.2 pg/ml; p<0.0001) and HCV-infected patients (1253.9+/-741.4 vs. 871.0+/-251.1 pg/ml; p=0.015). Whereas changes in serum APRIL levels were not significant among these groups, there was a significant correlation between BAFF and AST (R=0.278, p=0.003) or total bilirubin (R=0.363, p=0.0006) in PBC patients. Furthermore, serum BAFF levels were elevated in PBC patients with advanced interface hepatitis. Our data indicate that serum levels of BAFF and APRIL are differentially regulated and serum BAFF levels are significantly elevated in PBC patients. These findings suggest that BAFF may serve as a modulator of the clinical and/or serological manifestation in PBC patients.

Dynamic epidemiology of acute viral hepatitis in Japan.

The epidemiology of acute viral hepatitis (AVH) is dynamic and affected by many factors including hygiene, socioeconomic status and vaccination coverage. A total of 4,302 cases of AVH were sequentially enrolled in this nationwide study between 1980 and 2008. Of the cases of AVH, acute hepatitis A (AHA) accounted for 1,583 (36.8%), acute hepatitis B (AHB) for 1,197 (27.8%), acute hepatitis C (AHC) for 359 (8.3%), and non-A, non-B and non-C (non-ABC) for 1,163 (27.0%). Between 1980 and 1995, the proportions of AHA, AHB, AHC and non-ABC were approximately 40, 25, 10 and 25%; between 1996 and 2003, they were approximately 30, 30, 10 and 30%, and this shifted to approximately 10, 40, 10 and 40% in the last 5 years. The number of AHB caused by genotype A, which is not indigenous to Japan, was 6.0% between 1991 and 1996 but has been markedly increasing since 2000, to reach 52% in 2008. Autochthonous acute hepatitis E (AHE) accounted for 10-15% of non-ABC hepatitis after 2002. The etiology of AVH in Japan has been drastically changing. A marked increase of AHB genotype A and constant occurrence of autochthonous AHE require attention, and necessary measures should be taken.

Serum kynurenine levels are a novel biomarker to predict the prognosis of patients with hepatocellular carcinoma.

BACKGROUND: We examined serum kynurenine levels in patients with chronic hepatitis C virus infection, and the relationship between serum kynurenine and prognosis in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C. METHODS: We retrospectively analyzed 604 patients with HCC diagnosed between January 1999 and December 2015, and 288 patients without HCC who were seen at the National Hospital Organization Nagasaki Medical Center between October 2014 and November 2017. The association between serum kynurenine and prognosis was evaluated using the Cox's proportional hazards regression analysis. RESULTS: Patients with HCC had significantly higher values of serum kynurenine than patients without HCC (median: 557.1 vs. 464.2 ng/mL, p<0.001). Five-year survival rates of HCC patients with serum kynurenine ≥900 (n = 65), 600-899 (n = 194), and <600 ng/mL (n = 345) were 30.6%, 47.4%, and 61.4%, respectively (p = 0.001, log-rank test). Multivariate analysis identified serum kynurenine as an independent predictor for prognosis of HCC patients. The hazard ratio of serum kynurenine ≥900, and 600-899 compared with serum kynurenine <600 ng/mL were 1.91 (p<0.001) and 1.37 (p = 0.015), respectively. CONCLUSIONS: A high level of serum kynurenine correlated with poor prognosis of HCC. Serum kynurenine levels may be a novel biomarker to predict the prognosis of patients with HCC. The development of drugs that inhibit kynurenine production is expected to help improve the prognosis of patients with HCC.