Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.

Our results suggest that walking 5000 or more steps per day and maintaining a total energy intake of 30 kcal/IBW may serve as a reference for lifestyle guidelines for compensated cirrhotic patients.

Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), a-smooth muscle actin (a-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB-and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and a-SMA, whereas myofibroblasts around the portal vein expressed a-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, a-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB-and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express a-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become a-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.

Because of the chronic shortage of liver donors, hepatologists are required to prolong the liver transplant waiting period by preserving the hepatic reserve of scheduled recipients. This study examined the effectiveness of oral branched-chain amino acids (BCAAs), using outcome markers indicating pretransplant hepatic reserve. Fifty-six consecutive eligible patients with Child class A cirrhosis without major complications were randomly assigned to receive oral BCAA granules (12.45 g/day) for least 1 year or no BCAAs. Differences between groups in the Model for End-Stage Liver Disease (MELD) score, ChildTurcotte-Pugh (CTP) score, asialoscintigraphic clearance index (CI), and complications were examined. Of 50 remaining patients, 27 received BCAAs, and 23 received no BCAAs (mean duration, 3.2 years). The mean annual changes in the MELD score, CTP score, and asialoscintigraphic CI were smaller in the BCAA group than in the control group (Ϫ0.06 Ϯ 0.23 versus 0.10 Ϯ 0.40, P ϭ 0.024, 0.06 Ϯ 0.30 versus 0.30 Ϯ 0.48, P ϭ 0.037, and 0.00 Ϯ 0.02 versus 0.02 Ϯ 0.04, P ϭ 0.040, respectively). The mean annual changes in the serum total bilirubin and the serum albumin in the BCAA group were better preserved than those in the control group (Ϫ0.07 Ϯ 0.20 versus 0.12 Ϯ 0.18 mg/dL, P Ͻ 0.001, and 0.07 Ϯ 0.13 versus Ϫ0.02 Ϯ 0.19 g/dL, P ϭ 0.005, respectively); other laboratory variables were not significant. The incidence of overall major cirrhotic complications was lower in the BCAA group than in the control group [14.8% (4 of 27 patients) versus 30.4% (7 of 23 patients) at 3 years, P ϭ 0.043]; only ascites was significant individually. In conclusion, early interventional oral BCAAs might prolong the liver transplant waiting period by preserving hepatic reserve in cirrhosis. Liver Transpl 15:790-797, 2009. The 5-year survival rate after liver transplantation has recently been improved to 70% to 75%.1 Liver transplantation is the only means available for the radical treatment of severe liver cirrhosis. All patients with liver cirrhosis have the potential to become liver recipients in the near future. Furthermore, the 5-year survival rate Abbreviations: 99mTc-GSA, technetium-99m diethylenetriaminepentaacetic acid galactosyl human serum albumin; BCAA, branched-chain amino acid; CI, clearance index; CTP, Child-Turcotte-Pugh; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HGF, hepatocyte growth factor; MELD, Model for End-Stage Liver Disease; mTOR, mammalian target of rapamycin. The registration number is UMIN000001360

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drugdrug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8-((1-[ ]DPV (544 6 204 and 10.2 6 3.5 ml/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 ml/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CL uptake, liver and CL int, bile by 58% and 44%, respectively. These results suggest that PET imaging with [ 11 C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

Non-hospitalized cirrhotic patients may need to maintain an adequate dietary intake and receive lifestyle guidance to increase their physical activity levels.

Recently, the MICA rs2596542 and DEPDC5 rs1012068 variants in Japanese individuals as well as the HCP5 rs2244546 and PNPLA3 rs738409 variants in European individuals have been found associated with hepatocellular carcinoma (HCC). The present study determined which single nucleotide polymorphism (SNP) is the most predictive for developing hepatitis C virus (HCV)-related HCC in a Japanese cohort. Of the 4 SNPs analysed, only the MICA genotypes were significantly associated with development of HCC (p = 0.0185). The major (MA), hetero (HE), and minor (MI) genotypes occurred in 40%, 41%, and 19% of HCC patients and in 43%, 47%, and 10% of non-HCC patients, respectively. Interestingly, the MICA genotype was significantly correlated with MICA mRNA and soluble protein levels. In patients older than 70 years, the MI genotype was significantly associated with HCC development. In addition, the MI genotype was related to HCC development when the platelet count range was 10–15 × 104/μL, corresponding with the fibrosis stage; but not when the range was less than 10, indicating advanced fibrosis; or greater than 15 × 104/μL, as mild fibrosis. Thus, polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with HCC development in Japanese patients with chronic HCV infection.

No abstract