Aim:To compare the efficacy and safety of edoxaban and warfarin for treatment of portal vein thrombosis (PVT) following danaparoid sodium in patients with liver cirrhosis.Methods: Fifty cirrhotic patients with PVT treated initially for 2 weeks with danaparoid sodium were enrolled in this retrospective cohort study. Treatment was later switched to either edoxaban (n = 20) or warfarin (n = 30). We compared the efficacy and safety of edoxaban and warfarin for up to 6 months. The PVT volume was measured by dynamic computed tomography before treatment, at 2 weeks, and at 1, 3, and 6 months.

Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBPbinding element on the promoter ("autoloop regulatory circuit"), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms for PUFA suppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis. Polyunsaturated fatty acids (PUFA)3 have been well established as negative regulators of hepatic lipogenesis (reviewed in Ref. 1). Allmann and Gibson (2) discovered that adding 2% linoleate to a high carbohydrate fat-free diet suppressed the rate of hepatic fatty acid biosynthesis and the activities of fatty-acid synthase and glucose-6-phosphate dehydrogenase by nearly 70% in mice. In contrast, supplementing the high carbohydrate diet with palmitate, oleate, or cholesterol had no effect on hepatic lipogenesis or the activity of lipogenic enzymes. Since then, a number of investigators have demonstrated that dietary PUFA of the n-6 and n-3 families suppress hepatic lipogenesis. This anti-lipogenic action of PUFA reflects decreases in mRNA levels of hepatic enzymes, including acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase.The fatty acid biosynthetic pathway, composed of some 25 enzymes, has been elucidated in detail (3). For the de novo synthesis of long chain saturated fatty acids, fatty-acid synthase, the main synthetic enzyme that catalyzes the condensation of malonyl-CoA to produce the 16-carbon saturated fatty acid palmitate, and acetyl-CoA carboxylase, which synthesizes malonyl-CoA from acetyl-CoA, are of particular importance. The regulation of these lipogenic enzymes has been revealed to be primarily controlled by a transcription factor sterol regulatory element-binding protein (SREBP)-1c (4, 5).SREBPs are transcription factors that belong to the basic helix-loop-helix leucine zipper family and are considered to be profoundly involved in the transcriptional regulation of cholesterogenic and lipogenic enzymes (6, 7). Unlike other members of the basic helix-loop-helix leucine zipper family, SREBPs are synthesized as precursors bound to the endoplasmic reticulum and nuclear envelope. Upon activation, SREBPs are cleaved, and the N-terminal parts are released from the membrane into the nucleus as mature protein by a sequential two-step proteolytic processing. To date, three SREBP isof...

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The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10–196) and 23 (range 4–78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy.

Although the effect of levocarnitine (L‐carnitine) on hyperammonemia has been reported in patients with liver cirrhosis (LC), its effect on sarcopenia remains to be elucidated. We assessed the effects of L‐carnitine on sarcopenia in patients with LC. We retrospectively evaluated 52 patients with LC who were treated with L‐carnitine for more than 3 months between February 2013 and June 2017. Computed tomography was used to measure the cross‐sectional area of the skeletal muscles at the level of the third lumbar vertebra. The relative change in skeletal muscle index (SMI) per year (ΔSMI/year) was computed in each patient. We evaluated the relationship between ΔSMI/year and various parameters, such as age, sex, liver functional reserve, and dose of L‐carnitine. The median ΔSMI/year for all patients was −0.22%. The ΔSMI/year values in Child‐Pugh classes A, B, and C were not significantly different among the three groups. There was no significant relationship between ΔSMI/year and sex, age, body mass index, and sarcopenia. Multivariate analysis showed that only a high dose of L‐carnitine (odds ratio [OR], 4.812; 95% confidence interval [CI], 1.233‐18.784; P = 0.024) was associated with increased muscle mass. The L‐carnitine high‐dose group included a significantly larger number of patients with increased muscle mass compared with the low‐dose group (OR, 3.568; 95% CI, 1.138‐11.185; P = 0.027). Administration of L‐carnitine led to a significant and gradual reduction in serum ammonia levels. Conclusion: L‐carnitine seems to suppress the progression of sarcopenia dose dependently, and this was noted to be associated with the improvement of hyperammonemia in patients with LC.

Study approval. All experiments with mice were approved by the Ethics Review Committee for Animal Experimentation of the Graduate School of Biomedical Sciences, Hiroshima University (A18-64). All experiments with human samples were approved under NTUH-REC 201812063RINC and OHSRP 18-NIDDK-00585.

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OBJECTIVES: Biomarkers for optimizing the outcome of treatment with lenvatinib in patients with advanced hepatocellular carcinoma remain to be established despite intensive and comprehensive genomic research. Lenvatinib is characterized by its prominent inhibitory potency for fibroblast growth factor receptor (FGFR) 4 compared with earlier tyrosine kinase inhibitors. Thus, in this study, we focused on simplified quantification of FGFR4 in tumors as a potential predictive indicator. METHODS: According to The Cancer Genome Atlas data set curation, FGFR4 messenger RNA is broadly overexpressed in hepatocellular carcinoma in the absence of gene alteration. Gene set enrichment analysis revealed that the aggressiveness of the tumor was closely related to the FGFR4 level. To confirm the relationship between the benefits of lenvatinib and tumor addiction to the FGFR4 pathway, we analyzed protein levels in tumors and peripheral blood obtained from 57 prospectively registered patients treated with lenvatinib. RESULTS: Positive immunohistochemistry (>10% of tumor cells) for FGFR4 in biopsy samples before treatment was associated with a longer progression-free survival (2.5 vs 5.5 months, P = 0.01) and a favorable objective response rate (31% vs 81%, P = 0.006). By contrast, the concentration of soluble FGFR4 in peripheral blood as measured by an enzyme-linked immunosorbent assay was not associated with survival outcomes, because its fluctuations reflect hepatic fibrosis. Additional RNA sequencing analysis using archival surgical specimens (n = 90) suggested that alternative RNA splicing of FGFR4 in cancer may also explain this discrepancy. DISCUSSION: The tumor FGFR4 level was an independent predictor of response to lenvatinib.