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A 59-year-old woman presented to our hospital with liver dysfunction. Imaging revealed multiple lesions in the liver. The patient was diagnosed with peliosis hepatis using percutaneous and laparoscopic biopsies. However, her condition worsened with the appearance of new, obvious mass-forming lesions. Therefore, she underwent a second percutaneous biopsy of these lesions and was diagnosed with hepatic angiosarcoma. Her condition progressed rapidly, and she died two weeks after the diagnosis. Diagnosis of hepatic angiosarcoma in the early stages is difficult. It should be noted that hepatic angiosarcoma may be associated with the development of peliosis hepatis.

Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs.Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins.CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK.These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.

Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances NF erythroid 2-related factor 2 (NFE2L2) expression and that the interaction between IFN-γ and C-X3-C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFN-γ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFN-γ mRNA levels and positive correlations between IFN-γ and CX3CL1 mRNA levels post-UDCA treatment in PBC livers. NFE2L2-mediated transcriptional activation was significantly enhanced in UDCA-treated Jurkat cells. In 2-octynoic acid-immunized mice, IFN-γ production by liver-infiltrating T cells was dependent on NFE2L2 activation. IFN-γ significantly and dose-dependentlyinduced CX3CL1 expression, which was significantly decreased in HuCC-T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA-induced suppression of IFN-γ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver-infiltrating T cells in PBC.

Mongolia is a highly endemic region for chronic hepatitis B (HBV), hepatitis delta (HDV), and hepatitis C (HCV) infections. Aim of this study was to comprehensively characterize chronic viral hepatitis among Mongols living in Southern California. Three screening events were conducted between August and November 2018, with 528 adult Mongols tested for HBV and HCV. HBsAg (+) individuals (CHB) underwent additional testing for HDV RNA and anti-HDV. Liver tests, platelet count, and FibroScan™ were performed on CHB and chronic HCV (CHC) individuals. Fifty-one out of 534 were HBsAg reactive (9.7%), and all were foreign-born. Mean age of CHB individuals was 37.8 (range 18–69) years. Forty-six out of 51 were HBeAg (–). HBV genotypes were exclusively D2 or A1. Twenty-one out of 51 (41.2%) were anti-HDV (+) and 17/51 (33.3%) were HDV RNA (+). HDV RNA (+) individuals had significantly higher ALT, fibrosis-4 score, and liver stiffness compared to HDV RNA (–) individuals. Incidence of advanced fibrosis was higher in HDV RNA (+) individuals (57% vs. 13%, p = 0.013). Forty-eight (9.1%) individuals were anti-HCV (+) and 19 (3.6%) were HCV RNA (+). Mean age of CHC individuals was 40.2 (range 28–71) years. Prevalence of anti-HCV (+) was higher among those born between 1945 and 1965 versus those born after 1965 (18.8% vs. 7.9%, p = 0.025). Genotype 1b was predominant. Incidence of cirrhosis was 7% among all participants. Mongols living in the USA are at high risk for CHB and CHC infections. One-third of CHB individuals had CHD superinfection with advanced fibrosis. Universal screening for viral hepatitis in Mongols in the USA is mandatory.

Background/Aims: Changes in lipid profiles in patients in fected with hepatitis C virus (HCV) during direct-acting antivi ral therapy have been reported in recent years. However, the clinical aspects of disturbed lipid metabolism in chronic HCV infection have not been fully elucidated. Methods: Dynamic changes in serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and apolipoprotein levels in patients infected with HCV genotype 1b were exam ined during combination therapy with daclatasvir (DCV) and asunaprevir (ASV). Results: Total, LDL-, and HDL-cholesterol levels increased rapidly and persistently after week 4. Apoli poprotein (apo) A-I, apo B, apo C-II, and apo C-III levels were significantly higher at week 4 than at week 0. In contrast, apo A-II and apo E levels were significantly lower. The differences in LDL- and HDL-cholesterol levels were positively correlated with those of apo B and apo A-I, respectively. Interestingly, in patients with non-sustained virological response, these cholesterol levels decreased rapidly after viral breakthrough or viral relapse. Furthermore, similar changes were observed for apo A-I, apo B and apo C-III levels. Conclusions: Clear ance of HCV using combination therapy with DCV and ASV results in rapid changes in serum lipid profiles, suggesting an influence of HCV infection on disturbed lipid metabolism. (Gut Liver 2018;12:201-207)

Here we identified PUF60, a splicing factor and a U2 small nuclear ribonucleoprotein auxiliary factor, as a versatile regulator of transcriptional and post-transcriptional steps in expression of hepatitis B virus (HBV) 3.5 kb, precore plus pregenomic RNA. We demonstrate that PUF60 is involved in: 1) up-regulation of core promoter activity through its interaction with transcription factor TCF7L2, 2) promotion of 3.5 kb RNA degradation and 3) suppression of 3.5 kb RNA splicing. When the 1.24-fold HBV genome was introduced into cells with the PUF60-expression plasmid, the 3.5 kb RNA level was higher at days 1–2 post-transfection but declined thereafter in PUF60-expressing cells compared to viral replication control cells. Deletion analyses showed that the second and first RNA recognition motifs (RRMs) within PUF60 are responsible for core promoter activation and RNA degradation, respectively. Expression of PUF60 mutant deleting the first RRM led to higher HBV production. To our knowledge, this is the first to identify a host factor involved in not only positively regulating viral gene expression but also negative regulation of the same viral life cycle. Functional linkage between transcriptional and post-transcriptional controls during viral replication might be involved in mechanisms for intracellular antiviral defense and viral persistence.

Background Stent-stone complex (SSC) formation is one of the complications of endoscopic biliary stent placement. This study aimed to clarify the clinical characteristics and risk factors for SSC formation following plastic stent (PS) placement in patients with common bile duct (CBD) stones. Methods We retrospectively reviewed the charts of 78 patients with CBD stones who had undergone 107 biliary stent placements as palliative treatment. Demographic, historical, and stent-related data were collected and analyzed. Results At PS removal, SSC formations were observed in 18% of the 107 cases (SSC group) studied and not in the remaining 82% (non-SSC group). The duration of PS placement was significantly longer in the SSC group. The increase in CBD diameter during the stenting period as well as the incidence of cholangitis at PS removal was significantly greater in the SSC group. Multivariate analysis identified long-term (≥301 days) PS placement and the increase in CBD diameter during the stenting period as independent factors for SSC formation. Conclusions Long-term PS placement induces a risk of SSC formation in patients with CBD stones. The increase in diameter of CBD during the period of PS placement is a predictive factor for SSC formation in this situation.

OBJECTIVE Slow responders to pegylated interferon (Peg-IFN) and ribavirin (RBV) among patients infected with hepatitis C virus (HCV) genotype 1 may benefit from an extended treatment course. The aim of this study was to determine the efficacy of persistent negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy. METHODS A total of 46 HCV genotype 1-infected slow responders were treated for 72 weeks with Peg-IFN and RBV combination therapy alone (n=25) or additional long-term biweekly treatment with 90 μg of Peg-IFN-α2a (n=21). The criterion for the completion of long-term Peg-IFN monotherapy was defined as the attainment of constantly negative HCV RNA in the serum over 96 weeks during IFN treatment. RESULTS The patients with sustained negative serum HCV RNA during 96 weeks of IFN treatment had a higher rate of sustained virological response (SVR) than those without (81 vs. 40%, p=0.012). A multivariate analysis identified sustained negativity of serum HCV RNA over 96 weeks of IFN treatment to be a predictive factor for SVR. CONCLUSION In the present study, sustained negative serum HCV RNA over 96 weeks during long-term Peg-IFN monotherapy following 72 weeks of combination therapy of Peg-IFN and RBV resulted in beneficial virological outcomes among HCV genotype 1-infected slow responders.

Chronic infection with hepatitis C virus (HCV) is a global public health burden. It has been only several decades since this virus was first identified. In the meantime, a lot of progress has been made in the fight against HCV. Although the development of pegylated interferon (PEG-IFN) and its combination with ribavirin (RBV) has significantly increased effectiveness of IFN-based treatment, candidate patients must be assessed for eligibility prior to the treatment due to side effects of the regimens and the rates of sustained virological response (SVR) were only around 50%. In 2011, the protease inhibitor (PI) Telaprevir was firstly approved as a direct-acting antiviral (DAA) for hepatitis C. The second generation of PIs was subsequently introduced and, by adding PI to Peg-IFN/RBV, the SVR rates were found to be raised to up to 80%. Further, with the recent approval of the NS5A inhibitors and the NS5B polymerase inhibitors and with the SVR rates reaching 90% or greater using IFN-free, DAA combination regimens, it is now expected that the majority of patients with chronic hepatitis C can be cured of infection in the near future.

A 49-year-old man was diagnosed with severe acute pancreatitis because of pancreatic arteriovenous malformation (AVM). The pancreatic AVM spontaneously regressed during conservative treatment for severe acute pancreatitis. Transarterial embolization of an aneurysm in an artery branch flowing into the pancreatic AVM was performed using metallic coils, following amelioration of severe acute pancreatitis. The complete elimination of the pancreatic AVM was confirmed 1 year after embolization, and the patient has had no recurrence of pancreatic AVM and pancreatitis for over 6 years. Most cases of pancreatic AVMs with acute pancreatitis require surgical resection. This is a rare case in which the pancreatic AVM spontaneously regressed under the influence of acute severe pancreatitis.

The core promoter of hepatitis B virus (HBV) genome is a critical region for transcriptional initiation of 3.5 kb, pregenome and precore RNAs and for the viral replication. Although a number of host-cell factors that potentially regulate the viral promoter activities have been identified, the molecular mechanisms of the viral gene expression, in particular, regulatory mechanisms of the transcriptional repression remain elusive. In this study, we identified LUC7 like 3 pre-mRNA splicing factor (LUC7L3, also known as hLuc7A or CROP) as a novel interacting partner of HBV enhancer II and basal core promoter (ENII/BCP), key elements within the core promoter, through the proteomic screening and found that LUC7L3 functions as a negative regulator of ENII/BCP. Gene silencing of LUC7L3 significantly increased expression of the viral genes and antigens as well as the activities of ENII/BCP and core promoter. In contrast, overexpression of LUC7L3 inhibited their activities and HBV replication. In addition, LUC7L3 possibly contributes to promotion of the splicing of 3.5 kb RNA, which may also be involved in negative regulation of the pregenome RNA level. This is the first to demonstrate the involvement of LUC7L3 in regulation of gene transcription and in viral replication.

症例は68歳男性．C型肝硬変，多発肝細胞癌に対して肝動脈化学塞栓療法（transcatheter arterial chemoembolization：TACE）を繰り返していたが，2004年9月に腫瘍が左肝管内に浸潤を来たし化膿性胆管炎を併発した．左肝管の狭窄部に内視鏡的にplastic stent（PS）を留置し胆管炎は軽快したが，わずか23日で留置したPSが逸脱した．胆管炎再発を防ぐためにexpandable metallic stent（EMS）の留置を考えたが，出血などの合併症防止の目的で左肝管内に浸潤した腫瘍に対するTACEを先行させた．その後PSを抜去し，総肝管から左肝管にかけて8 mm径，80 mm長のS.M.A.R.T. Nitinol StentTMを留置した．2005年6月（初回のステント留置から309日後）に繰り返す発熱のため再度入院となった．computed tomography（CT）にて左葉B3の末梢に多発膿瘍形成が認められ，腫瘍のovergrowthに伴う胆管狭窄が原因と考えられた．このため前回留置したステントの上流にS.M.A.R.T. Nitinol StentTM，8 mm径，80 mm長の留置を追加した．本症例は2006年4月に肝不全で永眠されたが，それまでこのステントは開存しておりその間に感染や閉塞などの合併症は認めなかった．肝細胞癌は易出血性の腫瘍であるためEMS留置には出血や早期閉塞のリスクがあるとされるが，ステント留置前にTACEを行うことで出血やEMS閉塞を防ぐことができたと考えられた．

Background and Aims. To examine the changes in serum alpha-fetoprotein (AFP) levels after iron reduction by therapeutic phlebotomy in chronic hepatitis C patients. Methods. This retrospective study included 26 chronic hepatitis C patients. The patients were developed iron depletion by repeated therapeutic phlebotomies. Results. Iron reduction therapy significantly reduced the median level of serum AFP from 13 to 7 ng/mL, ALT from 96 to 50 IU/L, gamma-glutamyl transpeptidase (GGT) from 55 to 28 IU/L, and ferritin from 191 to 10 ng/mL (P<0.001 for each). The rate of decline in the AFP level correlated positively only with that in GGT (r=0.695, P=0.001), although a spurious correlation was observed between the rates of decline for AFP and ALT. The AFP level normalized (P=0.024). Conclusions. Iron reduction by therapeutic phlebotomy can reduce serum AFP and GGT levels in chronic hepatitis C patients.

A 73-year-old woman was admitted with gastrointestinal bleeding. She had undergone pylorus-preserving pancreaticoduodenectomy, hepaticojejunostomy and pancreatojejunostomy for pancreatic cancer a year earlier. Gastrointestinal endoscopy revealed bleeding from varices in an interposed jejunum. Enhanced CT showed an extrahepatic portal venous obstruction and cavernous transformation of the portal vein, which were complications of these operations. We performed endoscopic injection using α-cyanoacrylate monomer for the varices. After 4 treatments, the bleeding stopped. We concluded that endoscopic injection using α-cyanoacrylate monomer was effective and useful treatment for bleeding from hepatopetal varices, including cavernous transformation of the portal vein. This method is also useful in emergency situations.