Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

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.

Machine learning in primary biliary cholangitis: A novel approach for risk stratification.

BACKGROUND & AIMS: Machine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub-phenotyping and risk stratification in primary biliary cholangitis (PBC). METHODS: ML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver-related death or liver transplantation. ML and standard survival analysis were performed. RESULTS: The training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long-term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub-analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid-induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant-free survival. CONCLUSIONS: Unsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy-induced increase of albumin >1.2 x LLN should be considered a treatment goal.

Identification of microRNA-96-5p as a postoperative, prognostic microRNA predictor in nonviral hepatocellular carcinoma.

AIM: The microRNA (miR) clusters miR-183/96/182 and miR-217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC-HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC-HCC and analyze the antitumor effects of miR-96-5p. METHODS: The association between recurrence-free survival of 111 NBNC-HCC patients and the levels of miR-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, miR-216a-5p, and miR-216b-5p in tumor and adjacent tissues was investigated. The impact of miR-96-5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively. RESULTS: MicroRNA-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, and miR-216b-5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR-182-5p (p = 0.007) and miR-217-5p (p = 0.008) were associated with poor recurrence-free survival. In contrast, a low tumor/adjacent ratio of miR-96-5p (p < 0.001) was associated with poor recurrence-free survival. It suggested that further upregulation of miR-96-5p in tumors might have an inhibitory effect on recurrence. Transfection of miR-96-5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA-96-5p also suppressed proliferation and invasion, which inhibited epithelial-to-mesenchymal transition of HCC cells. CONCLUSION: MicroRNA-96-5p as a tumor suppressor would be valuable to stratify NBNC-HCC patients at high risk of recurrence.

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.

BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.

A validation study of the Ursodeoxycholic Acid Response Score in Japanese patients with primary biliary cholangitis.

BACKGROUND/PURPOSE: Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC. METHODS: Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase <1.67 times the upper limit of the normal value after 12 months of UDCA treatment. RESULTS: All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160). CONCLUSION: The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate.

Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10-8). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

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.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) producing large cell neuroendocrine carcinoma (LCNEC) of lung with multiple liver metastases: A case report.

A 78-year-old man was admitted to our hospital for multiple lung and liver tumors. Initial clinical diagnosis was hepatocellular carcinoma (HCC) with lung metastases because of a high value of serum protein induced by vitamin K absence or antagonist II (PIVKA-II) (6,705 mAU/mL). However, a review of a prior CT showed the lung tumor had existed 6 months before liver tumors were detected. The tumors progressed rapidly and the patient died 37 days after admission. Autopsy revealed that both lung and liver tumors exhibited the histology of large cell neuroendocrine carcinoma (LCNEC). Immunohistochemistry revealed that the tumor cells expressed not only neuroendocrine markers but also PIVKA-II diffusely. Hepatoid differentiation was not detected. Background liver did not show any chronic liver disease. The final diagnosis was PIVKA-II producing LCNEC of the lung with multiple liver metastases. PIVKA-II producing tumors other than HCC are extremely rare. To our best knowledge, this is the first case report of PIVKA-II producing neuroendocrine tumors of the lung.

Ganglionic acetylcholine receptor autoantibodies in patients with autoimmune diseases including primary biliary cirrhosis.

OBJECTIVES: Autonomic dysfunction is closely associated with autoimmune diseases (AID) including primary biliary cirrhosis (PBC). The objective of this study was to determine the prevalence of anti-ganglionic (nicotinic) acetylcholine receptor (gAChR) antibodies in patients with AID. METHODS: We determined the presence of gAChR antibodies in serum samples from 146 patients (systemic lupus erythematosus [SLE] = 32; rheumatoid arthritis [RA] = 43; systemic sclerosis [SSc] = 38; PBC= 33) without information regarding autonomic symptoms, as well as 34 patients with other neurological diseases [OND], and 73 healthy controls [HC]. We specifically analyzed sera for anti-gAChRα3 and -ß4 antibodies using the luciferase immunoprecipitation system (LIPS) assay. RESULTS: LIPS assay detected anti-gAChRα3 and -ß4 antibodies in the sera from patients with SLE (12.5%, 4/32), RA (18.6%, 8/43), SSc (13.2%, 5/38), PBC (9.1%, 3/33), OND (2.9%, 1/34), and HC (0.0%, 1/73). There were no significant correlations between the levels of anti-gAChRα3 and -ß4 antibodies, and the total titers of autoantibodies in AID. CONCLUSIONS: The results demonstrated a significant prevalence of anti-gAChR antibodies in patients with AID, which is independent of the production of other autoantibodies in patients with autoimmune diseases. These anti-gAChR antibodies could mediate the autonomic dysfunction involved in the autoimmune mechanisms of AID.

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.

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population.

We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

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.

Autoantibody status and histological variables influence biochemical response to treatment and long-term outcomes in Japanese patients with primary biliary cirrhosis.

AIM: The aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long-term outcomes in Japanese patients with primary biliary cirrhosis (PBC). METHODS: Biochemical response to ursodeoxycholic acid (UDCA) or UDCA plus bezafibrate was defined as good (≤upper limit of normal [ULN]), fair (≤1.5 × ULN) or poor (>1.5 × ULN) at 2 years after initiation of UDCA treatment. Associations between various factors (including age, sex, autoantibody status and histological variables at baseline), biochemical response to treatment and long-term outcomes were evaluated in 164 Japanese PBC patients. RESULTS: Anti-gp210 positivity and a higher bile duct loss score were significant risk factors for worse alkaline phosphatase (ALP) response (odds ratios [OR], 2.78 and 1.85, respectively). Age, anti-gp210 positivity and anticentromere positivity were significant risk factors for worse alanine aminotransferase (ALT) response (OR, 1.05, 4.0 and 2.77, respectively). Anti-gp210 positivity and a higher hepatitis score were significant risk factors for worse immunoglobulin (Ig)M response (OR, 2.10 and 2.06, respectively). Worse ALP and IgM response were significant risk factors for progression to late-stage disease without jaundice (OR, 2.27 and 2.32, respectively). Worse ALT response was a significant risk factor for progression to late-stage disease with persistent jaundice (OR, 11.11). CONCLUSION: Biochemical response to treatment at 2 years, which is influenced by autoantibody status and histological variables at baseline, can predict long-term outcomes in Japanese patients with PBC.

[Clinical guidelines for bone disease in primary biliary cirrhosis].

Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease and the association of osteoporosis is high. In this paper, the practical guidelines for PBC of Japan as well as those of America(AASLD)and Europe(EASL)are mentioned. Description of each guideline is essentially the same;taking sufficient calcium(1,000~1,200 mg/day)with vitamin D and weight-bearing exercise, and thereafter medication such as alendronate is recommended.

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.