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This study aimed to investigate the effects of interleukin-25, which belongs to the interleukin-17 family, on short-term high-fructose diet-induced hepatic triacylglycerol accumulation. Rats were fed a high-starch (control) or high-fructose diet for 7 d, with or without intraperitoneal administration of recombinant interleukin-25 from days 3-7. Treatment with interleukin-25 significantly reduced the mRNA levels and activity of fatty acid synthesis enzymes and caused a nominal reduction in hepatic triacylglycerol levels in rats fed a high-fructose diet but not in those fed a control diet. Interleukin-25 treatment did not affect the mRNA levels of β-oxidation enzymes in either the control or fructose-fed rats. These results suggest that treatment with interleukin-25 suppresses short-term high-fructose diet-induced fatty acid synthesis and leads to the alleviation of triacylglycerol accumulation in the liver.

The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. The cccDNA-specific ddPCR showed high accuracy with the dynamic range of cccDNA detection from 10 1 to 10 5 copies/assay. The ddPCR had higher sensitivity, specificity and precisely than qPCR. The results of ddPCR correlated closely with serum HB core-related antigen and HB surface antigen (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We demonstrated that in 2 PXB-mice after entecavir treatment, the total cccDNA content did not change during liver repopulation, although the cccDNA content per hepatocyte was reduced after the treatment. In the 6 patients with HBV-related hepatocellular carcinoma, ddPCR detected cccDNA in both tumor and non-tumor tissues. In 13 HBeAg-negative CHB patients with pegylated interferon alpha-2a, cccDNA contents from paired biopsies were more significantly reduced in virological response (VR) than in non-VR at week 48 (p = 0.0051). Interestingly, cccDNA levels were the lowest in VR with HBsAg clearance but remained detectable after the treatment. Collectively, ddPCR revealed that cccDNA content is stable during hepatocyte proliferation and persists at quantifiable levels, even after serum HBsAg clearance., (© 2022. The Author(s).)

Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency. However, the mechanism of hepatic Ggt regulation has not been explored fully. In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression of Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model. The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats. Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats. These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.

We examined effects of a major lipotrope, myo-inositol, on the expression of primary glycolytic (glucokinase and phosphofructokinase) and fructolytic enzyme (ketohexokinase [KHK] and aldolase B) genes in the livers of rats fed a control diet, high-sucrose diet, or high-sucrose diet supplemented with 0.5% myo-inositol for 14 d. Supplementation with myo-inositol decreased the hepatic expression of fructolytic enzyme genes, but not that of glycolytic enzyme genes, and the levels of triglycerides, fatty acid synthase, and KHK proteins in high-sucrose diet-induced fatty liver. The study results suggest that myo-inositol represses primary fructlysis, but not glycolysis, in high-sucrose diet-induced fatty liver.

ELOVL fatty acid elongase 6 (ELOVL6) is a long-chain fatty acid elongase, and the hepatic expression of the Elovl6 gene and accumulation of triglycerides (TG) are enhanced by long-term high-fructose intake. Fatty acid synthesis genes, including Elovl6, are regulated by lipogenic transcription factors, sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP). In addition, carbohydrate signals induce the expression of fatty acid synthase not only via these transcription factors but also via histone acetylation. Since a major lipotrope, myo-inositol (MI), can repress short-term high-fructose-induced fatty liver and the expression of fatty acid synthesis genes, we hypothesized that MI might influence SREBP-1c, ChREBP, and histone acetylation of Elovl6 in fatty liver induced by even short-term high-fructose intake. This study aimed to investigate whether dietary supplementation with MI affects Elovl6 expression, SREBP-1 and ChREBP binding, and acetylation of histones H3 and H4 at the Elovl6 promoter in short-term high-fructose diet-induced fatty liver in rats. Rats were fed a control diet, high-fructose diet, or high-fructose diet supplemented with 0.5% MI for 10 days. This study showed that MI supplementation reduced short-term high-fructose diet-induced hepatic expression of the Elovl6 gene, ChREBP binding, but not SREBP-1 binding, and acetylation of histones H3 and H4 at the Elovl6 promoter., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH., Methods: We enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA., Results: Serum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122-7471]) compared to those in CHC (1026 pg/ml [IQR: 806-1283] p<0.001), PBC (2395 pg/ml [IQR: 2012-3422] p<0.001) or healthy controls (1285 pg/ml [IQR: 1098-1812] p<0.001). In AIH group, serum sTIM-3 were correlated with alanine aminotransferase (ALT), or total bilirubin (TB) and negatively correlated with serum levels of albumin (Alb). Serum levels of sTIM-3 were also strongly correlated with Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum sTIM-3 levels (2147±623pg/ml versus 1321±378pg/ml, p<0.001)., Conclusions: Circulating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted., Competing Interests: KM has received grants from Chugai, Pfizer and AbbVie. Funds from these grants were not used for this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: The aim of this study was to investigate the potential of an intraoperative 3D hologram, which was a computer graphics model liver, with mixed reality techniques in liver surgery., Summary Background Data: The merits for the application of a hologram for surgical support are: 1) no sterilized display monitor; 2) better spatial awareness; and 3) 3D images shared by all the surgeons., Methods: 3D polygon data using preoperative computed tomography data was installed into head mount displays, HoloLens (Microsoft Corporation, Redmond, WA)., Results: In a Wi-Fi-enabled operative room, several surgeons wearing HoloLens succeeded in sharing the same hologram and moving that hologram from respective operators' angles by means of easy gesture-handling without any monitors. The intraoperative hologram contributed to better imagination of tumor locations, and for determining the parenchymal dissection line in the hepatectomy for the patients with more than 20 multiple colo-rectal liver metastases. In another case, the hologram enabled a safe Gliisonean pedicle approach for hepato-cellular carcinoma with a hilar anatomical anomaly. Surgeons could easily compare the real patient's anatomy and that of the hologram just before the hepatic hilar procedure., Conclusions: This initial experience suggested that an intraoperative hologram with mixed reality techniques contributed to "last-minute simulation," not for "navigation." The intraoperative hologram might be a new next-generation operation-supportive tool in terms of spatial awareness, sharing, and simplicity.

High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.

Background: The aim of this study was to evaluate the impact of pretreatment with bevacizumab on liver damage in a rat model of massive hepatectomy (Hx) model, as a surrogate model of massive Hx for liver metastasis from colorectal cancer., Materials and Methods: Male Wister rats (n=24) were separated into the following two groups: 90% Hx and 90% Hx plus bevacizumab group. Bevacizumab (5 mg/kg) was injected intraperitoneally 7 days before Hx. Samples of blood and remnant liver tissue were obtained 24 hours after hepatectomy and the following parameters were evaluated: Biochemical analysis; liver regeneration rate; survival rate; and real-time polymerase chain reaction for interleukin-1 beta (Il1b), tumor necrosis factor alpha (Tnfa), matrix metalloproteinase (Mmp) 2 and Mmp9 mRNA. In addition, samples of whole liver tissue were obtained immediately before Hx and real-time polymerase chain reaction was performed for X-box binding protein 1 (Xbp1), activating transcription factor 6 (Atf6), C/EBP homologous protein (Chop), glucose-regulated protein 78 (Grp78) and heat-shock protein 70 (Hsp70), as markers of endoplasmic reticulum stress response., Results: The levels of transaminases 24 hours after Hx were significantly reduced in the group pretreated with bevacizumab compared to that not pretreated (p<0.05). The liver regeneration rate at 24 hours after Hx was significantly increased in the group pretreated with bevacizumab compared with the group which underwent Hx alone (p<0.05). The survival rate for the group pretreated with bevacizumab tended to be higher than that of the Hx-only group, 72 hours after Hx (p=0.09). The expressions of Il1b, Mmp2 and Mmp9 mRNA 24 hours after Hx in the group pretreated with bevacizumab tended to be lower than that of rats which underwent Hx alone (p=0.11, 0.09 and 0.15, respectively). The expression of Xbp1, Chop, Grp78 and Hsp70 mRNA immediately before Hx in the group pretreated with bevacizumab were significantly higher than the 90% Hx group (p<0.05)., Conclusion: Bevacizumab pretreatment had protective effects on liver injury after massive hepatectomy in rats, apparently via the induction of the endoplasmic reticulum stress response, i.e. the so-called unfolded protein response., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Dietary supplementation with the major lipotrope myo-inositol (MI) potently reduces triglyceride (TG) content and expression levels of the fatty acid synthesis genes, for example, fatty acid synthase (FASN), in rat nonalcoholic fatty liver induced by high-fructose diet. Fatty acid synthesis genes are regulated by the carbohydrate-responsive element-binding protein (ChREBP) that exists in 2 isoforms: ChREBP-α and ChREBP-β. The gene encoding the latter isoform is more responsive to fructose. Because MI repressed the induction of fatty acid synthesis gene expression by high-fructose diet, we hypothesized that MI may reduce binding of ChREBP to the carbohydrate response elements (ChoREs) in the ChREBP-β gene as well as in fatty acid synthesis genes in the liver. Rats were fed high-glucose, high-fructose, or high-fructose diets supplemented with MI (0.05% and 0.25%) for 2 weeks. Hepatic TG content and expression levels of the glucose-6-phosphate dehydrogenase, malic enzyme 1, FASN, acetyl-CoA carboxylase alpha, S14, and ChREBP-β were remarkably elevated in rats fed with high fructose compared with the corresponding levels in high-glucose group. Notably, elevated values of these parameters in high-fructose group were reduced by MI. Similarly, high-fructose-induced ChREBP binding to the ChoREs of the ChREBP-β and FASN genes was nominally decreased by MI. This study showed that treatment with MI reduced elevated TG content and expression of genes related to fatty acid synthesis, such as FASN and ChREBP-β, in rat nonalcoholic fatty liver induced by high-fructose diet. Furthermore, MI treatment nominally decreased increased binding of ChREBP to the ChoREs of ChREBP-β and FASN genes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives:: We aimed to determine whether diffusion kurtosis imaging (DKI) analysis with the breath-hold technique can replace liver function results obtained from laboratory tests., Methods:: Patients (n = 79) suspected of having a hepatobiliary disease, and control group without liver diseases (n = 15) were examined with non-Gaussian diffusion-weighted imaging using a 3.0 T magnetic resonance imaging unit. Based on the findings of DKI, various blood serum parameters, including the indocyanine green (ICG) retention rate 15 min after an intravenous injection of ICG (ICG-R15) and mean kurtosis values and Child-Pugh and albumin-bilirubin (ALBI) scores, were calculated. In total, 17 patients were tested using ICG-R15. For evaluating liver function, correlations between the mean kurtosis value and the Child-Pugh score, ALBI score, and ICG-R15 value as indicators of liver function obtained from blood data were assessed using Spearman's rank correlation. In apparent diffusion coefficient as well, we assessed correlations with these indicators., Results:: The mean kurtosis value correlated with the Child-Pugh score (Spearman's rank-correlation coefficient, ρ = 0.3992; p < 0.0001). Moreover, the mean kurtosis value revealed a correlation with the ICG-R15 value (Spearman's rank-correlation coefficient, ρ = 0.5972; p = 0.00114). The correlation between the mean kurtosis value and the ALBI score was the poorest among these (Spearman's rank-correlation coefficient, ρ = 0.3395; p = 0.0008)., Conclusion:: Liver function correlating with the Child-Pugh score and ICG-R15 value can be quantitatively estimated using the mean kurtosis value obtained from DKI analysis. DKI analysis with the breath-hold technique can be used to determine liver function instead of performing laboratory tests., Advances in Knowledge:: Previous studies have not evaluated liver function in vivo using DKI.

Background: The effects of farnesoid X receptor (FXR) antagonists on plasma lipid profile in mice have not been investigated thus far. The aim of this study was to investigate the antidyslipidemic effects of an FXR antagonist in dyslipidemic mice, and to clarify the mechanisms underlying the lipid modulatory effect., Methods: Compound-T0 (1-100 mg/kg) was orally administered to C57BL/6J mice fed a Western-type diet or low-density lipoprotein receptor knockout (LDLR-/-) mice fed a Western-type diet for a week, and plasma lipid levels were investigated. Effects on lipid clearance, hepatic triglyceride secretion after Triton WR-1339 challenge, and intestinal lipid absorption were investigated after multiple dosing., Results: Compound-T0 significantly increased plasma level of non-high-density lipoprotein cholesterol in both C57BL/6 and LDLR-/- mice; in addition, it significantly increased plasma triglyceride level in LDLR-/- mice. Compound-T0 failed to enhance the clearance of 3,3'-dioctadecylindocarbocyanine (DiI)-labeled LDL in C57BL/6J mice. Although compound-T0 did not affect triglyceride clearance and hepatic triglyceride secretion, it significantly increased intestinal [ 3 H]cholesterol absorption in LDLR-/- mice., Conclusions: It was found that the FXR antagonist, compound-T0 exacerbated dyslipidemia in mice because it enhanced intestinal lipid absorption via acceleration of bile acid excretion., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Excessive fructose ingestion drastically enhances hepatic lipid accumulation. The most prominent form of inositol-myo-inositol (MI)-remarkably reduces high sucrose-induced hepatic triglyceride (TG) accumulation. Because MI is a major and strong lipotrope, we hypothesized in this study that MI improves fatty liver more induced by excessive ingestion of fructose than sucrose. Rats were fed a high-glucose diet (HGD), a high-fructose diet (HFD), or an HFD supplemented with 0.2% MI for 12 days. Hepatic levels of TG and mRNAs for fructolysis (ketohexokinase and aldolase B), lipogenesis (pyruvate kinase, liver, and RBC; glucose-6-phosphate dehydrogenase; acetyl-CoA carboxylase alpha; fatty acid synthase; and stearoyl-CoA desaturase 1), and a key transcription factor for lipogenesis-carbohydrate-responsive element-binding protein-were significantly increased in the HFD group compared with the HGD group, and the increase was markedly decreased by MI supplementation. Similarly, HFD-induced pyruvate kinase, liver, and RBC and fatty acid synthase protein levels in the liver were reduced by MI treatment. On the other hand, hepatic levels of mRNAs for β-oxidation (acyl-CoA synthetase and carnitine palmitoyltransferase 1a) did not differ among the 3 groups. Taken together, this study showed that MI supplementation decreases the expression of fructolytic/lipogenic genes and lipogenic proteins as well as TG accumulation in high fructose-induced fatty liver in rats., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aim: We assessed the utility of dynamic magnetic resonance imaging (MRI) with gadoxetate-ethoxybenzyl-diethylenetriamine penta-aceticpenta-acetic acid (Gd-EOB-DTPA) (EOB-MRI) for estimating functional liver volume compared to 99m Tc-galactosyl albumin single-photon-emission computed tomography ( 99m Tc-GSA SPECT)., Patients and Methods: Regional functional liver volume (left lateral, medial, right anterior, right posterior) of 58 hepatectomized patients was assessed using EOB-MRI and 99m Tc-GSA SPECT, and compared to the actual liver volume with MDCT-3D volumetry., Results: 99m Tc-GSA SPECT found a significantly lower functional volume of the left lateral section than the actual volume found by MDCT-3D volumetry (p=0.003) and EOB-MRI (p<0.001). Functional liver volume of right anterior section found with 99m Tc-GSA SPECT was significantly higher than that found by MDCT-3D volumetry (p=0.04), despite no differences in asialoglycoprotein receptor 1 (ASGR1) or ATP-dependent organic anion transporting polypeptide 1 (OATP) expression between the left lateral and right anterior sections., Conclusion: 99m Tc-GSA SPECT might underestimate the function of the left lobe and overestimate that of the right lobe. Therefore, EOB-MRI could be better for estimating the true regional functional liver reserve., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Overexpression of stathmin (STMN1) has been reported for several tumor entities. STMN1 expression correlated with the detection of mutant p53, also suggesting loss-of-function-dependent mechanisms for its accumulation in hepatocellular carcinoma (HCC) cells. On the other hand, miR-223 has been identified as one of the most down-regulated miRNAs in HCC, and its expression was shown to be negatively correlated with STMN1 expression. The aim of this study was to investigate the clinical significance of STMN1 and miRNA-223 expression., Patients and Methods: Fifty-six consecutive patients with HCC who underwent curative hepatectomy as initial treatment were enrolled. They were divided into two groups based on the STMN1 expression level: high (n=36) and low (n=20) gene-expression groups. We compared the clinicopathological factors between the groups with high and low expression in non-tumor tissues. Thirty out of 56 patients were also divided into groups with high (n=15) and low (n=15) miR-223 expression and compared the clinicopathological factors between the two groups., Results: There were no significant differences in patient background between high and low STMN1 expression groups. The incidence of multicentric (MC) recurrence in the high-expression group was significantly higher than in the low-expression group and high STMN1 expression was shown to be an independent risk factor for MC recurrence. There were also no significant differences in patient background between high and low miR-223 expression groups; however, the disease-free survival rate in the group with low expression was significantly worse. Furthermore, MC-related miRNAs identified by miRNA microarray clearly clustered patients into MC recurrence and non-recurrence groups., Conclusion: Both gene and miRNA expression profiles in non-tumor liver tissues could predict the risk for MC recurrence. Such molecular information may be useful in enabling better decision making for patients with HCC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI)., Methods: Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined., Results: Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group., Conclusion: DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest.

Introduction: During laparoscopic gastrectomy, it is important to establish a good operative field and ensure an adequate working space. The combined liver mobilization and retraction method is used to get a safe and optimal view., Methods: We retrospectively analyzed 32 consecutive patients who underwent laparoscopic total gastrectomy for gastric cancer. The patients were divided into two groups: the mobilization (+) group (n = 12) and the mobilization (-) group (n = 20). Hepatic function tests were performed in all patients., Results: Mobilization provided a satisfactory view of the working field, especially the gastroesophageal junction and the angle of His during laparoscopic total gastrectomy, and no complications were observed during liver retraction. On postoperative hepatic function testing, there was no significant difference between the two groups on any day., Conclusions: Combined liver mobilization and retraction may be helpful in laparoscopic total gastrectomy., (© 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Background and Aim: A remarkable feature of the liver is its regenerative capacity following partial hepatectomy. However, the regenerative capacity of many organs and tissues loses its natural ability to divide with aging. In this study, we investigated the association of aging with endoplasmic reticulum stress, the cell cycle, autophagy, and apoptosis-related genes during liver regeneration after hepatectomy., Methods: Balb/c 4-week and 40-week-old male mice were subjected to 70% hepatectomy. Animals were sacrificed at 24, 48, and 72 h after hepatectomy. Immunohistochemical stainings for proliferating cell nuclear antigen, LC3, Atg5, and caspase-3 were used to quantify protein expression. Real-time reverse transcription-polymerase chain reaction was used to detect p16, CHOP, LC3, Atg5, hepatocyte growth factor, cMet, cyclin D1, cyclin A2, and caspase-3 expression., Results: After hepatectomy, old group showed a lower survival rate and significantly lower expression of hepatocyte growth factor, cMet, cyclin D1, cyclin A2, proliferating cell nuclear antigen labeling index, and SMP30 compared with young group. The liver weight/body weight ratio was significantly lower at 48 h and 72 h after hepatectomy and was accompanied by markedly elevated levels of the liver cell injury markers, LC3 and caspase-3. Immunohistochemical results showed that LC3, Atg5, and caspase-3 protein expression were higher in old group than in young group., Conclusion: These results revealed that impaired liver regeneration was due to aging, which was expressed by decreased cell cycle and increased autophagy and apoptosis. Therefore, understanding the molecular basis for aged liver regeneration might provide a new therapeutic option for old patients., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) α promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARα by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.

Purposes: The number of patients with nonalcoholic fatty liver disease (NAFLD) is increasing. Hepatic steatosis is a major risk factor for hepatic failure after ischemia-reperfusion (I/R) injury. Hydrolyzed whey peptide (HWP) is a functional liquid-type nutritional diet containing whey peptide, which has previously been shown to exert anti-inflammatory effects. In the present study, we examined the effects of HWP on the hepatic I/R injury in a rat NAFLD model., Methods: Rats fed a methionine/choline-deficient diet for 4 weeks were divided into two groups after 30 min of whole liver ischemia. In Group-M, HWP was given immediately after reperfusion and every 6 h thereafter. In Group-C, the vehicle was given in the same manner. The liver function tests and microscopic findings of the liver after reperfusion were compared between the two groups., Results: The serum transaminase levels in Group-M were significantly lower than those in Group-C after reperfusion. The gene expression levels of IL-6 and inducible nitric oxide synthase (iNOS) were significantly lower in Group-M compared to Group-C. The TNF-α and uncoupling protein-2 (UCP-2) expression levels were also markedly lower in Group-M. The hepatic necrotic areas in Group-M were significantly smaller than those in Group-C., Conclusion: The administration of a HWP diet ameliorated the hepatic I/R injury in rats with NAFLD.

Purpose: Laparoscopic liver surgery is widely performed around the world, and surgeons recognize its feasibility. We herein report the current status of laparoscopic liver surgery in Japan., Methods: A questionnaire survey was conducted at 761 hospitals, including 41 member hospitals of the Japanese Endoscopic Liver Surgery Study Group and 720 facilities certified by the Japanese Society of Gastroenterological Surgery. Four hundred ninety-one hospitals responded to the questionnaire (response rate: 64 %). The data collected from 2,259 patients in 124 hospitals that reported performing laparoscopic liver resection were used. The surgical procedures and intraoperative complications, including the rate of conversion to open surgery, and morbidity rates were analyzed., Results: Pure laparoscopic procedures were performed in 1,346 patients (59.6 %), hand-assisted procedures in 174 (7.7 %) and hybrid procedures in 739 (32.7 %). Laparoscopic hepatectomy was performed in 1,982 patients (87.7 %): hemihepatectomy in 141 (7.1 %), sectionectomy in 87 (4.4 %), left lateral sectionectomy in 208 (10.5 %), segmentectomy in 91 (4.6 %) and non-anatomical partial resection in 1,248 (63.0 %). A total of 45 procedures (2.3 %) were converted to conventional open surgery. Postoperative complications occurred in 91 patients (4.6 %)., Conclusions: Laparoscopic liver surgery is a safe, feasible procedure for treating liver disease in carefully selected patients.

Background: Green tea catechin, especially epigallocatechin gallate (EGCG), is a well-known scavenger of reactive oxygen species and it may also function as an antioxidant through modulation of transcriptional factors and enzyme activities., Methods: Green tea extract (GTE®) which contained numerous EGCG was used. Wistar rats were performed 90 % hepatectomy and classified into 2 groups with (GTEHx, n = 25) or without GTE treatment (Hx, n = 25) and sacrificed at 1, 3, 7 and 14 days after operations. All rats had free access to drinking water supplemented with or without GTE from the 7th pre-operative day. Liver regeneration, hepatic inducible nitric oxide synthase (iNOS), anti-oxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)] and inflammatory markers [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNF-α)] were investigated., Results: The liver weight to body weight ratio (p < 0.01), proliferating cell nuclear antigen labeling index (p < 0.05) and phosphorylated extracellular signal-regulated kinase 1/2 (p < 0.05) at day 1 in the GTEHx group significantly increased compared to the Hx group. Hepatic iNOS levels at day 1 significantly decreased (p < 0.01) in the GTEHx group. Hepatic SOD, CAT and GSH-Px levels at day 1 significantly increased (SOD: p < 0.01, CAT and GSH-Px: p < 0.05) in the GTEHx group. In contrast, COX-2, NFκB and TNF-α levels at day 1 significantly decreased (COX-2: p < 0.01, NFκB and TNF-α: p < 0.05) in the GTEHx group., Conclusions: GTE pretreatment stimulated liver regeneration and improved liver damage after massive hepatectomy through anti-oxidative and anti-inflammatory effects. Green tea catechin might have the potential to attenuate liver dysfunction in early stage after massive hepatectomy.

Objective: Perioperative nutritional care is important to maintain preoperative and postoperative nutritional status. However, few reports have investigated energy metabolism after hepatectomy. The aim of this study was to determine differences in energy metabolism, blood biochemistry, and nutritional status before and after liver resection in patients with hepatocellular carcinoma (HCC) and healthy living donors for liver transplantation., Methods: Eighteen hospitalized patients with HCC group and 13 living donors for liver transplantation (donor group) were enrolled in this study. The donor group was divided into two groups on the basis of age; Y-donor group (age < 40 y, n = 7), and O-donor group (age ≥ 40 y, n = 6). Energy metabolism was measured by indirect calorimetry at preoperative day and postoperative day (POD) 7 and 14, and blood biochemistry was also examined., Results: Recovery of non-protein respiratory quotient (npRQ) and blood biochemical data such as total bilirubin, aspartate aminotransferase and alanine aminotransferase levels were observed in Y-donor group on POD 14. However, although biochemical data improved in the HCC and O-donor group, npRQ remained unchanged on POD 14., Conclusions: Improvement of npRQ took longer than blood biochemical data in patients with HCC and older donors. Because the recovery of npRQ is associated with donor age, careful nutritional management may be required for a longer time depending on the pathophysiological condition of each patient after hepatectomy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We aimed to elucidate the mechanism underlying the anti-dyslipidemic effect of compound-T3, a farnesoid X receptor antagonist, by investigating its effects on hepatic lipid metabolism in non-human primates. We administered lipid-lowering drugs for 7 days to cynomolgus monkeys receiving a high-fat diet, and subsequently measured the levels of lipid parameters in plasma, feces, and hepatic tissue fluids. Compound-T3 (0.3 and 3mg/kg p.o.) significantly decreased the plasma levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B in a dose-dependent manner. It also decreased the mRNA levels of hepatic small heterodimer partner-1, induced the mRNA expression of hepatic cholesterol 7α-hydroxylase, reduced hepatic cholesterol and triglyceride levels, increased fecal bile acid excretion, and upregulated the expression of hepatic low-density lipoprotein (LDL) receptor. Furthermore, compound-T3 significantly increased plasma HDL cholesterol and apolipoprotein A-I levels. The mRNA expression levels of hepatic apolipoprotein A-I tended to increase after compound-T3 treatment. Compound-T3 also induced accumulation of hepatic bile acids and decreased the mRNA expression levels of the hepatic bile acid export pump. The effects of cholestyramine (300mg/kg p.o.) on the plasma and hepatic lipid parameters were similar to those of compound-T3, and it increased fecal bile acid levels without causing accumulation of hepatic bile acids. These findings suggest that LDL receptor-mediated hepatic LDL incorporation due to cholesterol catabolism catalyzed by cholesterol 7α-hydroxylase decreases plasma non-HDL cholesterol levels. Upregulation of hepatic apolipoprotein A-I mRNA expression may partially contribute to the increase in HDL cholesterol levels mediated by compound-T3., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Glucose intolerance characterized by postprandial hyperglycemia and hyperinsulinemia is commonly seen in patients with liver cirrhosis (LC). The aim of this study is to clarify the relation between glucose intolerance and disorder of liver function in patients with LC. The 75 g oral glucose tolerance test (75 g OGTT) and the hyperinsulinemic euglycemic clamp combined with 0.2 g/kg oral glucose load (HECGL) were conducted in 61 patients with LC. Based on the results of 75 g OGTT, the 61 patients with LC were divided into groups, 21 (34.4%) patients with normal glucose tolerance (LC-NGT), 12 (19.7%) patients with impaired glucose tolerance (LC-IGT) and 28 (45.9%) patients with diabetes mellitus (LC-DM). Fasting plasma glucose (FPG) level was normal in 50 (82.0%) patients with LC. All patients with LC showed insulin resistance in both peripheral (skeletal and adipose) and hepatic tissues evaluated by HECGL, although significant correlation between the degree of glucose intolerance and the severity of hepatic dysfunction was not observed. Insulin resistance in both liver and peripheral tissues is the early sign in the patients with LC. This fact indicates that nutritional care from early stages of LC would be necessary in the patients.

Purpose: Blood vessel (BV) information can be used to guide body organ segmentation on computed tomography (CT) imaging. The proposed method uses abdominal BVs (ABVs) to segment the liver through the portal phase of an abdominal CT dataset. This method aims to address the wide variability in liver shape and size, separate liver from other organs of similar intensity, and segment hepatic low-intensity tumors (LITs)., Methods: Thin ABVs are enhanced using three-dimensional (3D) opening. ABVs are extracted and classified into hepatic BVs (HBVs) and nonhepatic BVs (non-HBVs) with a small number of interactions, and HBVs and non-HBVs are used for constraining automatic liver segmentation. HBVs are used to individually segment the core region of the liver. To separate the liver from other organs, this core region and non-HBVs are used to construct an initial 3D boundary surface. To segment LITs, the core region is classified into non-LIT- and LIT-parts by fitting the histogram of the core region using a variational Bayesian Gaussian mixture model. Each part of the core region is extended based on its corresponding component of the mixture, and extension is completed when it reaches a variation in intensity or the constructed boundary surface, which is reconfirmed to fit robustly between the liver and neighboring organs of similar intensity. A solid-angle technique is used to refine main BVs at the entrances to the inferior vena cava and the portal vein., Results: The proposed method was applied to 80 datasets: 30 Medical Image Computing and Computer Assisted Intervention (MICCAI) and 50 non-MICCAI; 30 datasets of non-MICCAI data include tumors. Our results for MICCAI-test data were evaluated by sliver07 (http://www.sliver07.org/) organizers with an overall score of 85.7, which ranks best on the site as of July 2013. These results (average ± standard deviation) include the five error measures of the 2007 MICCAI workshop for liver segmentation as follows. Results for volume overlap error, relative volume difference, average symmetric surface distance, root mean square symmetric surface distance, and maximum symmetric surface distance were 4.33 ± 0.73, 0.28 ± 0.87, 0.63 ± 0.16, 1.19 ± 0.28, and 14.01 ± 2.88, respectively; and when applying our method to non-MICCAI data, results were 3.21 ± 0.75, 0.06 ± 1.29, 0.45 ± 0.17, 0.98 ± 0.26, and 12.69 ± 3.89, respectively. These results demonstrate high performance of the method when applied to different CT datasets., Conclusions: BVs can be used to address the wide variability in liver shape and size, as BVs provide unique details for the structure of each studied liver. Constructing a boundary surface using HBVs and non-HBVs can separate liver from its neighboring organs of similar intensity. By fitting the histogram of the core region using a variational Bayesian Gaussian mixture model, LITs are segmented and measuring the volumetry of non-LIT- and LIT-parts becomes possible. Further examination of the proposed method on a large number of datasets is required for clinical applications, and development of the method for full automation may be possible and useful in the clinic.

Background and Aim: Possible spleno-hepatic relationships affected by hepatectomy still remained unclear. We have previously reported that splenectomy may ameliorate liver injuries and promote appropriate liver regeneration after massive hepatectomy. Therefore, we investigated the effects of splenectomy on the DNA expression profile in the liver after massive hepatectomy in rats., Methods: Rats were divided into the following two groups: 90% hepatectomy (Hx group) and 90% hepatectomy with splenectomy (Hx + Sp group). Rats were sacrificed 3 and 6 h after surgery, and mRNA from liver tissue was isolated and hybridized to Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix, Santa Clara, CA, USA) and a pathway analysis was done with Ingenuity Pathway Analysis (Ingenuity Systems, Mountain View, CA, USA)., Results: We determined the Hx + Sp/Hx ratio to assess the influence of splenectomy, and cut-off values were set at more than 2.0-fold or less than 1/2 (0.5)-fold. Immediate early response gene including early growth response-1 and FBJ murine osteosarcoma-related pathways were markedly downregulated by splenectomy. In contrast, heme oxygenase-1 gene-related pathway was upregulated by splenectomy., Conclusions: Splenectomy provided the protective effects for liver failure and promoted liver regeneration, possibly owing to the downregulation of immediate early response genes and upregulation of the heat shock protein, heme oxygenase-1., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Purpose: To clarify the functional involvement of hedgehog signaling, especially sonic hedgehog (Shh) and glioma-associated oncogene (Gli)-1 which are known to play an important role in embryonic development and cancer, in the regeneration of a hepatectomized rat liver., Methods: Six-week-old male Wistar rats were subjected to 70 or 90 % hepatectomy (Hx). Animals were killed at 24, 48 and 72 h after Hx. The liver/body weight ratio was measured as an index of regeneration. Formalin-fixed liver samples were embedded in paraffin, stained for immunohistochemistry with proliferating cell nuclear antigen (PCNA) antibody, and the labeling index was calculated. Immunohistochemistry was also performed with Shh and Gli-1 antibodies., Results: The liver/body weight ratio gradually increased in both the 70 and 90 % Hx, groups. The hepatocytes were strongly stained for PCNA at 24 h after Hx. Non-parenchymal cells were gradually stained by PCNA from 24 to 72 h after Hx. Shh and Gli-1 expression in hepatocytes was higher after 24 h than at other times and then gradually decreased. Shh and Gli-1 expression in non-parenchymal cells increased gradually, and was found mainly in liver zone I at 72 h after 70 and 90 % Hx., Conclusions: The expression of both markers suggested that Shh signaling contributes to tissue reconstruction after Hx.

Background/aims: The impact of pegylated-interferon (PEG-IFN) α-2b on liver regeneration has not yet been elucidated., Methodology: Rats were divided into the following four groups: 70% hepatectomy (Hx); 70% Hx+PEG-IFN; 90% Hx and 90% Hx+PEG-IFN group (n=6 each). Rats were pretreated with subcutaneous of PEGIFN α-2b (1.5 μg/kg) administration 24 hours before Hx. Samples were taken 24, 48 and 72 hours after Hx and the following parameters were investigated: blood analysis (AST, WBC, PLT); liver weight to body weight ratio (Lw/Bw ratio); survival and PCNA labeling index (LI)., Results: In the 90% Hx model, there was no significant difference between the Hx+PEG-IFN group and the Hx alone group in blood analysis; AST after postoperative 24 hours (2511 vs. 2466 IU/L), WBC (1200 vs. 1290) and PLT (107 vs. 111 x 10⁴/mm³), in Lw/Bw ratio at postoperative 0, 24, 48, 72 hours, respectively (0.38, 0.60, 1.14, 1.69 vs. 0.37, 0.64, 1.12, 1.63), in postoperative survival (40% vs. 45%), and in PCNA LI at postoperative 0, 24, 48, 72 hours, respectively (10.4%, 16.8%, 14.6%, 12.8% vs. 10.0%, 17.1%, 15.6%, 13.7%). In the 70% Hx model, there was no significant difference between the Hx+PEG-IFN group and the Hx alone group for all parameters., Conclusions: Our data demonstrated that PEG-IFN α-2b did not affect liver regeneration and the early use of PEG-IFN α-2b would cause no problems after liver transplantation using partial grafts including living donor liver transplantation.

Background: Preoperative estimation of the liver functional reserve is important in liver surgery. We evaluated the role of dynamic magnetic resonance (MR) imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), i.e., EOB-MRI, for determining liver functional reserve., Methods: Fifty patients who underwent EOB-MRI to examine their liver tumors were included in this study. We first performed a pixel-by-pixel comparison of registered MR images and activity images with Tc-99m galactosyl human serum albumin (GSA) on each slice, and the correlation coefficient was calculated for 8 patients. We also determined the correlation coefficient between the relative signal intensity (SI) values of EOB-MRI and preoperative liver function, such as the GSA, indocyanine green dye retention at 15 min (ICGR15), and prothrombin time., Results: The mean of the correlation coefficients for 512 × 512 matrices between the EOB-MRI and the GSA was 0.83 ± 0.05 (ranging from 0.73 to 0.87). The correlation coefficient between the relative SI of the EOB-MRI and the receptor index (LHL15) of GSA was 0.56 (P < 0.01). Better correlation coefficients were observed between the relative SI and the liver function test, including ICGR15 (r = -0.67, P < 0.01) and prothrombin time (r = 0.59, P < 0.01). In a patient with hilar cholangiocarcinoma whose right hepatic duct was obstructed, the relative SI in the right lobe (2.4 ± 0.3) was significantly lower than that in the left lobe (3.1 ± 0.1)., Conclusion: EOB-MRI represents a practical and reliable imaging technique that may be used to estimate regional liver functional reserve in the clinical setting.

The liver hanging maneuver (LHM) is a useful technique to transect the liver parenchyma while lifting it with a tape passed between the anterior surface of the inferior vena cava (IVC) and the liver parenchyma. The original method was employed mostly for right hepatectomy with an "anterior approach" for huge liver tumors. The tape serves as a guide to the transection plane and facilitates the control of bleeding in the deeper parenchyma of the liver while protecting the anterior surface of the IVC. On the other hand, several recent studies have shown the feasibility and usefulness of modified LHM techniques. These methods can be applied to left hepatectomy with or without caudate lobectomy (segmentectomy 1), even for patients undergoing orthotopic liver transplantation. This report explains the methods and pitfalls of the original and modified LHM. In addition, important anatomical and technical aspects of the mobilization of hepatic lobes are also included.

Background: Ischemia-reperfusion injury has been demonstrated in a variety of clinical settings. The morbidity associated with liver transplantation and major hepatic resections is partly a result of ischemia-reperfusion injury. Follistatin, an activin-binding protein, binds to activins and subsequently blocks their action. It was reported that blockade of the action of activin with administration of follistatin accelerates recovery from ischemia renal injury. This study was conducted to investigate the involvement of the activin-follistatin system in hepatic ischemia-reperfusion injury., Methods: Total hepatic ischemia for 30 min was performed followed by reperfusion in a rat model. Rats were divided into two groups: a follistatin group and a control group. Follistatin (1 μg/body), which is an activin-binding protein, was administered at the time of reperfusion., Results: Though 80% of animals survived in the follistatin group, four of five animals died in the control group within 3 days after reperfusion (p<0.05). AST was significantly lower at 3 h after reperfusion in the follistatin group (p<0.05). LDH was also lower at 6 h after reperfusion in the follistatin group (p<0.05). Follistatin inhibited the mRNA expression of the βA subunit of activin. Moreover, the expression of IL-6, which is an inflammatory cytokine, was suppressed at 6 h after reperfusion in the follistatin group (p<0.05)., Conclusions: The present study demonstrated that treatment with follistatin reduced the expression of IL-6 and activin resulting in beneficial support for hepatic ischemia-reperfusion injuries.

Elevated circulating alanine aminotransferase (ALT) and γ-glutamyltransferase (γ-GTP) activities, and the accumulation of fat, particularly visceral fat, in healthy and preclinical subjects reportedly increase the risk for metabolic diseases such as diabetes. In the present study, we examined the associations between these hepatic enzymes and the total visceral and subcutaneous fat area, and for both regions of fat independently, in healthy and preclinical middle-aged Japanese men. We conducted a cross-sectional study of men who participated in health check-ups in Japan. We removed participants, who were diagnosed with metabolic diseases at the time of the health check-up. Three hundred fifteen subjects aged 40-64 y (mean±SD, 50.5±6.9 y) were selected. We compared associations between the total visceral and subcutaneous fat area, and for both regions independently, with various clinical parameters, including hepatic enzyme markers, using Spearman's rank correlation coefficient analysis and multiple linear regression analysis. The total visceral and subcutaneous fat area and both regions independently were positively associated with body mass index, systolic and diastolic blood pressure, fasting blood glucose, total cholesterol, low-density lipoprotein cholesterol, aspartate aminotransferase, ALT and γ-GTP. ALT and γ-GTP activities were the strongest explanatory variables for increased visceral fat area, independent of the subcutaneous fat area. In contrast, these hepatic enzymes were not explanatory variables for increased subcutaneous fat area. The results of the present study show that the accumulation of visceral fat is positively associated with ALT and γ-GTP activities independently of subcutaneous fat area in healthy and preclinical Japanese men.

Elevated circulating alanine aminotransferase (ALT) and γ-glutamyltranspeptidase (γ-GTP) activities in healthy and preclinical subjects are associated with increased risk for obesity, diabetes and related complications. In the present study, we examined the associations between these hepatic enzymes and circulating cytokines as markers for insulin sensitivity (adiponectin) and inflammation [interleukin-6 (IL-6)] in middle-aged Japanese men not being treated for metabolic diseases. We conducted a cross-sectional study of 310 Japanese men aged 40-69 y (mean ± SD, 58.8 ± 7.6 y) who were not being treated for metabolic diseases and who participated in health checkups in Japan. We analyzed their lifestyle factors, clinical factors, and plasma adiponectin and IL-6 concentrations. We determined associations between the concentrations of these cytokines and the clinical and lifestyle factors using Spearman's correlation analysis, Jonckheere-Terpstra's test and multiple linear regression. ALT activity was negatively associated with adiponectin (r=-0.302, p<0.001) but not with IL-6. γ-GTP activity was positively associated with IL-6 (r=0.335, p<0.001) and negatively associated with adiponectin (r=-0.129, p<0.05). Aspartate aminotransferase (AST) activity was positively associated with IL-6 (r=0.131, p<0.05) and negatively associated with adiponectin (r=-0.125, p<0.05). Multiple linear regression analyses showed that adiponectin was independently and negatively associated with ALT activity, while IL-6 was independently and positively associated with γ-GTP activity. Adiponectin and IL-6 were not independently associated with AST activity. The results of this study indicate that circulating ALT activity is negatively associated with adiponectin concentration, γ-GTP is positively associated with increased IL-6 concentration, and AST is not associated with these cytokines in middle-aged Japanese men not being treated for metabolic diseases.

Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS-398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS-398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS-398 treatment. In the 90% PH model, administration of NS-398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver.

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to tumor metastases or recurrence even after undergoing potentially curative treatment. There are two types of HCC recurrence. The early and late tumor recurrences appear in distinct biological contexts, and their clinical courses are quite different. Therefore, it is important to precisely and distinctly discriminate the risk of each type of HCC recurrence. Many researchers have used DNA microarray technology to reclassify HCC with respect to its malignant potential. Some of these studies successfully identified specific gene-expression signatures derived from the cancerous tissues of HCC for predicting the early recurrence due to intrahepatic metastasis. However, there are no well-defined predictors for late recurrence. Recently, a few studies have focused on the nontumorous portion of liver tissues to predict late recurrence, possibly due to de novo hepatocarcinogenesis based on the idea of "field cancerization." This study reviewed the possible value of a gene-expression analysis of noncancerous liver tissue to clarify the risk for multicentric late recurrence of HCC. These findings may have important implications for chemopreventive strategies and tailored surveillance programs. Furthermore, this approach may also be applicable to other multifocal tumors, such as head and neck carcinoma.

The optimal administration of immunosuppressants such as tacrolimus (Tac) for small-for-size (SFS) grafts, where the functional liver mass is small and must regenerate, has not been reported so far. The aim of this study is to clarify the characteristics of Tac metabolism according to liver volume. Seven-week-old male Wistar rats were randomly divided into three groups: (1) Tac administrated and 70% Hx group (Tac 70% Hx group), (2) Tac administrated and 90% Hx group (Tac 90% Hx group), and (3) vehicle administrated and 90% Hx group (control 90% Hx group). In both the Tac groups, Tac (0.3 mg/kg) was given daily for 3 days before operation, and daily after surgery until sacrifice (each time point; n = 5). The plasma concentration of Tac (trough level), as well as liver toxicity, were measured. The plasma concentration of Tac in the Tac 90% Hx group was significantly higher than in the Tac 70% Hx group from 24 to 72 h after operation. Furthermore, expression of CYP3AII mRNA was significantly lower in the Tac 90% Hx group than in the Tac 70% Hx group. Regarding the liver toxicity, there was no significant difference in both the Tac 90% Hx and the control 90% Hx groups. In this experimental study, the plasma concentration of Tac was dependent on the remnant liver volume. Therefore, special attention in regard to Tac administration should also be taken for patients with SFS grafts in living-donor liver transplantation (LDLT).

Background: The liver sometimes has an accessory middle or inferior right hepatic vein (RHV) in addition to the usually existing superior RHV. In liver surgery, it is important to know the parenchymal drainage volume of these accessory RHVs to avoid postoperative liver dysfunction caused by blood congestion. The purpose of this study was to determine methods to estimate parenchymal drainage volume of such accessory veins., Methods: By reviewing the preoperative multidetector-row computed tomography (MDCT) and using specialist software, we investigated the presence of accessory RHVs, the diameter, and the parenchymal drainage volume of each vein, and we determined correlations between the diameter and parenchymal drainage volume of the accessory RHVs., Results: Middle (median diameter, 4.9 mm) and inferior (median diameter, 5.0 mm) RHVs were present in 15% and 47%, respectively, in this study. The median parenchymal drainage volume of the superior, middle, and inferior RHVs was 401 mL, 64 mL, and 116 mL, respectively. There were positive correlations between diameters and the parenchymal drainage volume of accessory RHVs (middle RHV: y = 27.1x-45.7, r = .78, P < .05; inferior RHV: y = 34.8x-57.8, r = .80, P < .01), which made it possible to calculate the parenchymal drainage volume of these veins using their diameters alone., Conclusion: Approximately half of the livers in this study had 1 or 2 accessory RHV(s), the parenchymal drainage volume of which was substantial. We can calculate the parenchymal drainage volume from the diameter of each accessory RHV on CT, which enables liver surgeons to determine how to manage these hepatic veins.

Background: Procurement of left lobe (LL) living donor graft with medial right lobe (mRL) might be an innovative technique., Methods: The grafts were procured from a living donor, exposing the right anterior Glissonean pedicles, after confirmation of the demarcation line by test-clamping of the right Glissonean pedicle. Based on serial computed tomography, the increase in the graft volume (GV) after addition of mRL and changes in volumes were evaluated., Results: The addition of mRL (n=7) increased GV by 48+/-9 g, which corresponded to a 4% increase in GV-to-standard liver volume ratio. After transplantation, mRL volume has increased in all cases. The regeneration rate of the mRL and other LL segments 1 month after transplantation was 61%+/-18% and 146%+/-15%, respectively. Viable hepatic parenchyma with marginal bile duct dilatations in transplanted mRL was observed in all the cases. Marginal enhancement was observed in those cases with promoted regeneration of transplanted mRL. In the cranial part of the mRL, portal branching from the left portal vein, over the middle hepatic vein, was observed in all cases., Conclusion: This technique affords an increase in GV in living donor LL procurement, and should increases the application of LL grafts in living donor liver transplantation.

Background: To ensure donor safety in adult-to-adult living donor liver transplantation, we established a selection criterion for donors in which left lobe (LL) was the first choice of graft., Methods: Two hundred six consecutive donors were retrospectively studied. Donors were divided into two groups according to graft type: LL graft (n=137) and right lobe (RL) graft (n=69)., Results: Although mean intraoperative blood loss of LL was significantly increased compared with RL, mean peak postoperative total bilirubin levels and duration of hospital stay after surgery were significantly less for LL than RL (P<0.05). No donor died or suffered a life-threatening complication during the study period. The overall complication rate was 34.0%, including biliary complications in 5.3%. The number of biliary complications was four (2.9%) in LL and seven (10.1%) in RL (P<0.05). Logistic regression analysis revealed that only graft type (LL vs. RL) is significantly related to the occurrence of biliary complications (odds ratio 0.11; P=0.0012). The cumulative overall graft survival rates in the recipients with LL were not significantly different from that in the recipients with RL., Conclusions: LL grafting should be considered favorably when selecting donors for adult-to-adult living donor liver transplantation.

Flutamide is used for prostate cancer therapy but occasionally induces severe liver injury. Flutamide is hydrolyzed in the body into 5-amino-2-nitrobenzotrifluoride (FLU-1) and then further oxidized. In our previous study, N-hydroxy FLU-1 (FLU-1 N-OH) was detected in the urine of patients and exhibited cytotoxicity in rat primary hepatocytes. In the present study, we have assessed the roles of FLU-1 N-oxidation and hepatic glutathione (GSH) depletion in liver injury. FLU-1 (200 mg/kg p.o.) was administered to C57BL/6 mice for 5 days together with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) (3 mg/kg i.p.) for the first 3 days. Mice were fasted for the last 2 days to deplete hepatic GSH. Administration of FLU-1 alone did not affect serum alanine aminotransferase activities (ALT), whereas coadministration of FLU-1 and TCPOBOP significantly increased ALT in fasted mice but not in nonfasted mice. Microsomal FLU-1 N-hydroxylation was enhanced approximately 5 times by TCPOBOP treatment. Flutamide metabolite-protein adducts were detected in liver microsomes incubated with FLU-1 N-OH, but not with FLU-1 and flutamide, by immunoblotting using antiflutamide antiserum. In the presence of mouse liver cytosol, FLU-1 N-OH was reduced back into FLU-1. This enzymatic reduction required NAD(P)H as a cofactor. The reduction was enhanced by the coexistence of NAD(P)H and GSH, whereas it was markedly inhibited by allopurinol (20 microM). By using purified bovine xanthine oxidase, the reduction was observed in the presence of NAD(P)H. These results suggest that FLU-1 N-OH is involved in flutamide-induced hepatotoxicity and that cytosolic reduction of FLU-1 N-OH plays a major role in protection against flutamide-induced hepatotoxicity.

We investigated the characteristics of gadoxetate disodium (Gd-EOB-DTPA) as a contrast agent for magnetic resonance imaging of the mouse liver. Mice were imaged sequentially under isoflurane anesthesia using a T1-weighted, three-dimensional fast low-angle shot (3D FLASH) sequence after an intravenous injection of Gd-EOB-DTPA or gadobenate dimeglumine (Gd-BOPTA), and the time course of the contrast effect was examined. The time course of the contrast effect of Gd-EOB-DTPA was also assessed after intravenous injection under pentobarbital anesthesia and after subcutaneous injection while awake or under isoflurane or pentobarbital anesthesia. Moreover, different doses of Gd-EOB-DTPA or Gd-BOPTA were injected subcutaneously into conscious mice, and the clarity of the liver border was evaluated visually. Intravenous injection under isoflurane anesthesia caused rapid contrast enhancement in the liver with both Gd-EOB-DTPA and Gd-BOPTA, and the contrast effect was 41% stronger with Gd-EOB-DTPA. Subcutaneous injection of Gd-EOB-DTPA caused delayed but favorable contrast enhancement in the liver. Washout of Gd-EOB-DTPA was faster in mice injected while awake than in those injected under anesthesia. After intravenous injection, washout was faster under pentobarbital anesthesia than under isoflurane anesthesia. The peak liver contrast was 11% and 18% stronger under pentobarbital anesthesia than under isoflurane anesthesia, after intravenous and subcutaneous injections, respectively. Subcutaneous injection of Gd-EOB-DTPA or Gd-BOPTA caused dose-dependent contrast effects in the liver. At a given dose, the contrast effect tended to be stronger and liver demarcation tended to be clearer with Gd-EOB-DTPA than with Gd-BOPTA. In conclusion, intravenous or subcutaneous injection of Gd-EOB-DTPA produces a favorable contrast effects in the mouse liver, indicating its potential in investigating mouse models of liver diseases. The contrast effects vary between conscious mice and anesthetized mice and among anesthetic agents used.

Background/aims: The postoperative survival rate is dependent on the invasive depth of the gallbladder carcinoma. When this carcinoma has invaded beyond the subserosal layer, lymph node and adjacent organ involvement is found in a large number of patients, and long-term survival cannot be achieved. The aim of this study is to establish a surgical strategy for advanced gallbladder carcinoma according to the invasive depth., Methodology: A retrospective analysis was conducted of 44 patients with the gallblader carcinoma. The invasive depth was histologically defined by the Japanese Society of Biliary Surgery system as follows. (hinf0: within muscle layer, hinf1a: subserosal layer, hinf1b: hepatic infiltration within 5 mm, hinf2.3: hepatic infiltration more than 5 mm), Results: Wedge resection of the gallbladder bed was performed in 5 cases, and in four of the five patients (80%), intrahepatic recurrence occurred within 6 months. S4a+S5 subsegmentectomy of the liver is performed in 11 cases (hinf0,1a/b:n=5, hinf2,3:n=6) and the postoperative survival rate was significantly better in cases of hinf0,1a/b (p<0.05). In cases of hinf2,3 an extended hepatic lobectomy (n=5) tended to obtain a better survival rate, compared with S4a+S5 subsegmentectomy (n=6)(p=0.13)., Conclusions: S4a+S5 subsegmentectomy of the liver is a standard operation for GB carcinoma with subserosal invasion.

Fluvastatin, the first entirely synthetic statin, has a significant cholesterol-lowing effect comparable with other statins. In addition, it has been shown to inhibit oxidative stress and improve vascular endothelial function. The aim of this study was to clarify the pretreatment effects of fluvastatin on liver function after massive hepatectomy in rats. Six-week-old male Wister rats were divided into two groups: a fluvastatin group (group F), pretreated with oral administration of fluvastatin (20 mg/kg per day) for 2 days before 90% hepatectomy; and a control group (group C), pretreated with vehicle for 2 days before hepatectomy. Animals were sacrificed at 0, 12, 24, 48, and 72 h after hepatectomy. The liver regeneration rate, liver function tests, and hepatic stellate cell activation were examined. The liver regeneration rate in group F was significantly higher at 72 h after hepatectomy (P < 0.05). The serum level of total bilirubin in group F was significantly lower at 48 h after hepatectomy (P < 0.05). Sinusoidal area in group F was maintained histologically. Furthermore, the expression of alpha smooth-muscle actin (alpha-SMA) protein in the liver was inhibited in group F at 48 h after hepatectomy. This study demonstrated the beneficial effects of fluvastatin in a lethal massive hepatectomy model using rats, with improved hepatic regeneration and microcirculations, by inhibiting the activation of hepatic stellate cells.

No reliable model for predicting early graft function and patient survival after living donor liver transplantation (LDLT) exists. The aim of this study was to establish a new formula for predicting early graft function and prognosis using technetium-99m galactosyl-human serum albumin (Tc-GSA) liver scintigraphy. The ratio of the hepatic uptake ratio of Tc-GSA to the clearance index of Tc-GSA (LHL/HH) was determined 7 days after LDLT. There were 22 patients with a ratio greater than 1.3 and 6 patients with a ratio less than 1.3. Graft function on the 14th postoperative day (POD) was compared between the 2 groups. A new formula to predict the LHL/HH score was established as follows: LHL/HH (predictive score) = 0.011 x graft weight (%) - 0.016 x donor age - 0.008 x Model for End-Stage Liver Disease score - 0.15 x shunt (if present) + 1.757 (r(2) = 0.497, P < 0.01). This predicted LHL/HH ratio was compared to the graft function on POD 14 for 110 LDLT patients. The total bilirubin (TB) and prothrombin time international normalized ratio (PT-INR) in the group with an LHL/HH score > or = 1.3 were lower than those in the group with an LHL/HH score < 1.3. The TB, PT-INR, and volume of ascites in the group with a predictive score > or = 1.3 (n = 86) were lower than those in the group with a score < 1.3 (n = 24). The 6-month survival probability was improved in the group with a predictive score > or = 1.3. In conclusion, this preoperative calculated LHL/HH score is correlated with graft function and short-term prognosis. Thus, this predictive model may allow transplant surgeons to use a living donor left lobe graft with greater confidence.

Background/aims: Left lobe graft is an ideal option to minimize potential risk for the donor in adult living-donor liver transplantation (LDLT). However, its use is restricted due to size limitations. The purpose of this study was to determine the impact of a new technique for the acquisition of additional liver volume for left lobe graft., Methodology: Three donors underwent left hepatic lobectomy by exploiting a new technique as follows: a demarcation line was marked by clamping the right first Glisson's pedicle. A parenchymal transection plane was located 1 cm right side from the demarcation line and just on the left side of the right anterior Glisson's pedicle. A part of the anterior segment added to the left lobe graft by this procedure belonged to right anterior segment by preoperative CT. The preoperative volumetry of the liver was performed using the 3D-CT software, which was able to calculate total liver volume and the volume of each vessel's territories. Additional liver volume was calculated by preoperative CT scan and defined as part of the perfusion area by the right anterior portal branch. Blood perfusion of the additional liver area was postoperatively assessed by dynamic CT, and graft outcome was also evaluated., Results: An additional gain ranged from 40 mL to 51 mL (mean 41.8 mL). GV/SLV was 35.7, 60.0, and 41.0%. The rate of additional volume in GV/SLV ranged from 7.2-8.4% (mean 7.6%). All grafts functioned well. The CT scan performed on early postoperative period confirmed excellent blood perfusion the additional segment. No complication attributable to small-for-size graft was noted., Conclusions: This new technique for left lobe graft harvesting proved a promising approach to gain additional volume, thereby avoiding small-for-size graft in adult LDLT.

Living donor liver transplantation (LDLT) between adults inevitably implies two potential risks associated with a small-for-size graft for the recipient and small remnant liver for the donor. To overcome these problems, LDLT using dual grafts from two independent donors can be a solution, in which sufficient graft volume can be obtained while preserving donor safety. We present a case of LDLT that was managed successfully by using right and left lobe dual grafts from two donors. The recipient was a large-size male with hepatitis C cirrhosis complicated by multiple hepatocellular carcinomas (HCCs). The first donor donated a right lobe graft and the second donor donated a left lobe plus caudate lobe graft with the middle hepatic vein. Graft function was excellent throughout the course without evidence of small-for-size syndrome. In conclusion, LDLT using dual grafts can be justified in a selected case to avoid small-for-size graft problems without increasing independent donor risks.

Background/purpose: The efficacies of vessel sealing system (VSS) devices for major Glisson bundles and major bile ducts have not yet been determined., Methods: Male pigs (n = 6) and a LigaSure V device and an Atlas 20 (Valleylab, Boulder, CO, USA) device were used in this study. After laparotomy, the common bile duct and the right and left first-degree Glisson bundles were sealed by the VSS. The lower and upper parts of the common bile ducts were also sealed. Macro-and microscopic examinations were performed for the analysis of specimens taken just after VSS application. In an analysis of bile duct specimens taken 1 week after the VSS application, both burst pressure tests and histological examinations were performed., Results: (1) In the analysis of the specimens (Glisson bundles and bile ducts) obtained just after the VSS application, the macroscopic changes included permanent, flattened changes of the Glisson bundles and bile ducts, without showing any blood or bile leakage. Histological examination of the transverse sections of the Glisson bundle after VSS application revealed that not only the blood vessels but also the bile ducts were fused together. (2) In the analysis of the specimens (bile ducts) obtained 1 week after the VSS application, second-look laparotomy showed extrahepatic bile duct obstruction. The mean burst pressure of the sealed bile ducts was 74.4 +/- 20.1 mmHg. Histological examination revealed that the lumen of the bile duct was completely sealed and the duct was surrounded by dense connective tissues., Conclusions: The VSS is useful for the safe sealing of not only the major Glisson bundles but also the major bile ducts.

Objectives: To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH)., Materials: One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16., Methods: DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the daily alcohol intake was >20 g [8/18 (44.4%)] compared with those <20 g [0/10 (0%)] (p < 0.05), indicating that alcohol is a risk factor for DIH in C-CH patients treated with INH, RFP and PZA., Conclusions: In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.