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We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure.This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed.The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to1.3 by day 8.Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR1.3 after 1 week could reflect prognostic improvement.

AIM This study aimed to demonstrate the feasibility of identifying candidates of portopulmonary hypertension (PoPH) from general portal hypertension patients based on chest computed tomography (CT) results. METHODS One hundred and thirty patients with portal hypertension who had undergone interventional radiology therapies at our hospital between August 2011 and July 2021 were included, and preoperative clinical data were collected. Suspicious PoPH was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or the ratio of mPA-D to ascending aorta diameter (mPA-D/aAo-D) ≥ 1.0, and probable PoPH as mPA-D ≥ 33 mm based on the chest CT. Prevalence of suspicious and probable PoPH was evaluated, and the differences in clinical characteristics of each population were compared. RESULTS Overall, 29 (22.3%) and 5 (3.8%) patients were categorized as suspicious and probable PoPH, respectively. Univariate analyses revealed that female sex, higher shortest diameter of inferior vena cava, presence of portosystemic shunts ≥ 5 mm, and lower blood urea nitrogen levels were significantly associated with suspicious PoPH (P < 0.05). Multivariate analysis identified all four factors as significantly independent determinants of suspicious PoPH (P < 0.05). In addition, among the population of suspicious PoPH, there were significant differences in seven parameters, including total bilirubin levels and spleen volume between patients with and without probable PoPH (P < 0.05). However, no significant independent indicators of probable PoPH were found. CONCLUSIONS CT-based measurements of mPA-D and mPA-D/aAo-D have the potential to screen patients with suspicious PoPH in clinical practice focused on portal hypertension. This article is protected by copyright. All rights reserved.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Aim To describe a case of hepatitis C virus-related decompensated cirrhosis with portal-systemic liver failure and refractory encephalopathy that was successfully managed with a combination of interventional radiology and pharmacotherapy to improve hepatic function including hyperammonemia and to control portal-splenic venous hemodynamics with hepatic venous pressure gradient (HVPG) monitoring. Case presentation A man in his late 50s presented with a Child-Pugh score of 13, Model for End-Stage Liver Disease-sodium (MELD-Na) score of 19, and blood ammonia level of 185 μg/dL. He underwent balloon-occluded retrograde transvenous obliteration (BRTO) followed by partial splenic embolization (PSE) and non-selective beta-blocker (NSBB) administration. BRTO induced drastic changes in the portal-splenic venous hemodynamics, resulting in dramatically improved hepatic function and reduced hyperammonemia. However, the procedure resulted in increased HVPG from 13.6 mmHg at baseline to 23.5 mmHg at 1-month post-BRTO, accompanied by ascites retention and portal hypertensive gastropathy (PHG) development. Thereafter, PSE was performed, followed by NSBB administration, to control the elevated portal venous pressure following BRTO. Postoperatively, the patient's ascites and PHG improved after splenic artery embolization, which eventually disappeared after the additional administration of NSBBs at 1 month later. The HVPG finally decreased to 16.9 mmHg, and Child-Pugh score, MELD-Na score, and blood ammonia level improved to 7, 11, and 22 μg/dL, respectively, after all therapies. Conclusion BRTO significantly improved the symptoms of portal-systemic liver failure with refractory encephalopathy. PSE and NSBB administration could contribute to additional amelioration of hepatic function and successful management of complications induced by portal hemodynamic changes following BRTO.

BACKGROUND AND AIM This study aimed to identify predictors of model for end-stage liver disease sodium score reductions and improvements in vital prognoses following portosystemic shunt occlusion in portal hypertension patients. METHODS Seventy cirrhotic patients with major portosystemic shunts and a mean model for end-stage liver disease sodium score of 10.5 underwent balloon-occluded retrograde transvenous obliteration between February 2008 and March 2017. We calculated the scores before and 1 month after shunt occlusion. The long-term outcomes were monitored, and vital prognoses were analyzed. RESULTS The model for end-stage liver disease sodium score did not change significantly 1 month post-balloon-occluded retrograde transvenous obliteration, and the score decreased postoperatively in 31 (44.3%) patients. Univariate analyses showed that decline in the score after portosystemic shunt occlusion was strongly associated with hepatic encephalopathy as a procedural indication, lower liver volumes, and lower liver stiffness levels measured by transient elastography before treatment (P

Aim To compare the clinical characteristics of patients with hepatic encephalopathy (HE) and those with gastric varices (GV) before and after balloon-occluded retrograde transvenous obliteration (BRTO). Methods Eighty cirrhotic patients who underwent BRTO, including 42 men and 38 women, and whose mean age was 68 years, comprised the HE (n = 18) and GV (n = 62) groups. The patients' data before and 1 month after BRTO were analyzed. Results Before BRTO, the groups did not differ in their portal flow volume (PFV) or hepatic venous pressure gradient (HVPG). The portal vein (PV) was narrower and the splenic vein (SpV) was wider in the HE group than in the GV group. The SpV flow was hepatofugal in 75.0% of HE patients and hepatopetal in 92.6% of GV patients. The Child-Pugh (CP) score of the HE group was significantly higher than that of the GV group pre-BRTO. After BRTO, the PFV and HVPG increases in the HE group equaled those in the GV group, and the PV dilation was similar in both groups. Conversely, the SpV was significantly contracted for HE patients, but significantly dilated for GV patients. Postoperatively, the SpV flow was hepatopetal in all patients. Compared to that in the GV group, the CP score decreased markedly in the HE group, and no significant increases in complications occurred post-BRTO for HE patients. Conclusions The HE patients showed distinct portal-splenic hemodynamics before and after BRTO. Balloon-occluded retrograde transvenous obliteration markedly improved hepatic function in the HE group compared with the GV group.

Aim To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, a multicenter pilot survey was carried out to examine the usefulness of overseas criteria in patients with chronic liver diseases manifesting acute decompensation. Methods Patients fulfilling the Asian-Pacific Association for the Study of the Liver (APASL), European Association for the Study of the Liver (EASL), or Chinese Medical Association (CMA) criteria for decompensation were enrolled from eight institutions in Japan, and the clinical features were evaluated. Results Among 112 patients, 109 patients (97.3%) fulfilled the APASL criteria for decompensation; 7 patients were excluded because the decompensation had been provoked by gastrointestinal bleeding. Consequently, 102 patients (91.1%) were diagnosed as having ACLF according to the APASL definition. Among the patients who fulfilled the APASL criteria for decompensation, the etiologies of the underlying liver diseases were alcohol abuse in 59 cases (54.1%) and hepatitis B or hepatitis C virus infection in 24 (22.0%). The acute insults were alcohol abuse in 50 (45.9%), bacterial infection in 26 (23.9%), and exacerbation of underlying liver disease in 14 (12.8%). Fifty-four patients (49.5%) satisfied the CMA criteria, but the survival rates were similar between patients who did and those who did not meet the criteria. When 84 patients with underlying cirrhosis were classified according to the EASL-Chronic Liver Failure (Clif) Consortium criteria, the survival rates differed according to grade: 67.6% (23/34) for patients without ACLF, and 41.2% (14/34) and 18.8% (3/16) for those with grade 1/2 and grade 3 ACLF, respectively. Conclusion The APASL definition was suitable for screening Japanese patients with ACLF, including those whose conditions were triggered by gastrointestinal bleeding, and the EASL-Clif Consortium criteria were useful for predicting outcome.

To establish diagnostic criteria for acute-on-chronic liver failure (ACLF) in Japan, the Intractable Hepato-Biliary Disease Study Group of Japan undertook a multicenter pilot survey for patients fulfilling the Asian Pacific Association for the Study of the Liver (APASL), Association for the Study of the Liver-Chronic Liver Failure (EASL-Clif) Consortium, or Chinese Medical Association (CMA) diagnostic criteria for ACLF. The APASL criteria were suitable for screening Japanese patients with ACLF when patients whose conditions were triggered by gastrointestinal bleeding were included within the disease entity, and the EASL-Clif Consortium criteria were useful for classifying the severity of the patients' conditions. Based on these observations, the Study Group proposed the following diagnostic criteria for ACLF in Japan: patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having ACLF when a deterioration of liver function (serum bilirubin level ≥5.0 mg/dL and prothrombin time value ≤40% of the standardized values and/or international normalization rate ≥1.5) caused by severe liver damage develops within 28 days after acute insults, such as alcohol abuse, bacterial infection, gastrointestinal bleeding, or the exacerbation of underlying liver diseases. The severities of the patients can be classified into four grades depending on the extent of the deterioration in organ functions, including kidney, cerebral, blood coagulation, circulatory and respiratory functions, as well as liver function. The usefulness of these novel criteria should be validated prospectively in a large-scale cohort in the future.

Aim The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. Methods Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18-36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. Results In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH3 ) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. Conclusion The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia.

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery-embolic agent, the drug-eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB-TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB-TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71-year-old woman was admitted to our hospital to undergo DEB-TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB-TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB-TACE is rare, there may be increased potential for hemobilia when DEB-TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB-TACE may be contraindicated for such cases.

Idiopathic portal hypertension (IPH), causing aberrant portal hemodynamics, is a disease with an as yet unidentified cause and no treatment has been established so far. The Japanese research group on IPH in Japan was set up in 1975 by the Ministry of Health, Labour and Welfare, furthermore extra-hepatic portal obstruction (EHO) and Budd-Chiari syndrome (BCS) have been added to the research subjects and further work has continued. The aims of the research group are to accurately evaluate the current status of the three diseases in Japan, elucidate the disease aetiology and pathogenesis, and develop new treatments. Due to the long-term efforts of the Japanese research group, aberrant portal hemodynamics has been investigated to date in a variety of aspects, from epidemiological and pathological studies to molecular biology analysis. As a result, it has been shown that there are abnormal genes in the liver, specific for IPH. In addition, pathological findings of BCS were internationally compared and the difference in findings between Japan and Western countries has been clarified. Furthermore, it was found that complication rates of hepatocellular carcinoma (HCC) in BCS were higher in Japan. Based on the research, "Diagnosis and treatment of aberrant portal hemodynamics (2001)", including diagnostic criteria for aberrant portal hemodynamics, was published in 2001. In 2013, it was revised to "Diagnosis and treatment guidelines for aberrant portal hemodynamics (2013)" after the incorporation of diagnosis and treatment in accordance with its current status. This article is protected by copyright. All rights reserved.

Aim Loop diuretics and spironolactone are used in patients with hepatic edema, but they are sometimes associated with insufficient responses as well as adverse events. Tolvaptan, a vasopressin type 2 receptor antagonist, was approved for hepatic edema in 2013. A large-scale post-marketing surveillance study has been carried out to evaluate the effectiveness and safety of tolvaptan in real-world clinical settings. Methods Patients with hepatic cirrhosis with insufficient response to conventional diuretics were enrolled. The observational period was up to 6 months. Changes in body weight and clinical symptoms were measured to evaluate effectiveness. The incidence of adverse drug reactions was summarized as a safety measure. Results Of 970 patients enrolled, 463 were included in the safety analysis. Of this group, 340 were included in the effectiveness analysis. Decreases in body weight from baseline were −2.38 kg on day 7 and −3.52 kg on day 14. Ascites and bloated feeling was significantly improved within 14 days. The mean change in body weight depended on estimated glomerular filtration rate levels. The most frequently reported adverse drug reaction was thirst (6.9% of patients). Serum sodium level of ≥146 mEq/L was observed in 12 patients (2.7%). Conclusions In the real-world clinical setting, tolvaptan showed aquaretic effectiveness in patients with cirrhosis. The mean change in body weight depended on renal function. We recommend tolvaptan use for hepatic cirrhosis at a stage in which the renal function is maintained.

The present study investigated the effect of a DNA demethylating agent, decitabine, against Epstein-Barr virus-associated gastric cancer (EBVaGC). Decitabine inhibited cell growth and induced G2/M arrest and apoptosis in EBVaGC cell lines. The expression of E-cadherin was up-regulated and cell motility was significantly inhibited in the cells treated with decitabine. The promoter regions of p73 and RUNX3 were demethylated, and their expression was up-regulated by decitabine. They enhanced the transcription of p21, which induced G2/M arrest and apoptosis through down-regulation of c-Myc. Decitabine also induced the expression of BZLF1 in SNU719. Induction of EBV lytic infection was an alternative way to cause apoptosis of the host cells. This study is the first report to reveal the effectiveness of a demethylating agent in inhibiting tumor cell proliferation and up-regulation of E-cadherin in EBVaGC. J. Med. Virol. 89:508-517, 2017. © 2016 Wiley Periodicals, Inc.

Aim Alcoholic hepatocellular carcinoma (ALD-HCC) accounts for the majority of non-B non-C HCC (NBNC-HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC-HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC-HCC patients with modest alcohol consumption. Methods From 2007 to 2010, 2283 HCC patients were evaluated at 10 hospitals. We collected detailed etiology data of 588 NBNC-HCC patients and compared the clinical characteristics and prognosis between ALD-HCC and modest alcohol-HCC patients. Results There were 69 HCC patients with modest alcohol consumption, accounting for 3% of all HCC patients evaluated. This patient group had significantly more women and higher prevalence of Child–Pugh class A, hypertension and advanced disease stage, and were diagnosed with HCC at an older age than the ALD-HCC group (266 patients). Additionally, among the modest alcohol-HCC patients, diabetes was significantly more common in the anti-hepatitis B core (HBc) negative subgroup than in the anti-HBc positive subgroup. However, no significant difference in survival was observed between the two patient groups regardless of significant differences in tumor staging. Alcohol consumption and metabolic factors were not significant independent predictors of survival. Conclusion The clinical characteristics of modest alcohol-HCC included advanced staging, favorable liver reserve capacity and older age at diagnosis. HCC development in patients with modest alcohol consumption may relate to metabolic factors. Although approximately 30% of the evaluated HCC cases were in advanced stages, the prognosis of NBNC-HCC patients with modest alcohol consumption was relatively favorable.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non-invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

AIM Less invasive therapies using mesenchymal stem cells (MSC) are being developed to treat patients with severe liver cirrhosis. MSC constitute a promising cell source for regenerative therapy and are frequently isolated from bone marrow (BMSC) or adipose tissue (ASC). Therefore, this study assessed the characteristics of these two cell types and their safety for cell infusion. METHODS In vitro, exhaustive genetic analysis was performed using human (h)BMSC and hASC. Subsequently, the expression of mRNA and protein was evaluated. In vivo, mouse (m)BMSC or mASC was infused into serial mice via the peripheral vein, and 24-h survival rate, prothrombin time and cause of death were analyzed. RESULTS On polymerase chain reaction, western blotting, enzyme-linked immunoassay and fluorescence-activated cell sorting, tissue factor was found to be expressed at higher levels in hASC than in hBMSC. Prothrombin time in mice infused with mASC (>120 s) was markedly longer than that of untreated mice (6.5 ± 1.7 s) and that of mice infused with BMSC (6.7 ± 0.8 s) (P

In 2011, the Intractable Liver Diseases Study Group of Japan, established novel diagnostic criteria for "acute liver failure ", and published the classification criteria for the etiologies of acute liver failure and late-onset hepatic failure (LOHF) in 2013. According to this classification, HBV carriers showing acute hepatitis exacerbation were divided into 3 subgroups; asymptomatic or inactive HBV carriers without drug exposure, asymptomatic or inactive HBV carriers developing HBV reactivation during and after immunosuppressive therapies and/or antineoplastic chemotherapies and those with previously resolved HBV infection showing iatrogenic HBV reactivation. In an annual nationwide survey in 2013, however, a patient with previously resolved HBV infection was enrolled, in whom LOHF developed as a result of HBV reactivation despite in the absence of immunosuppressive therapies and/or antineoplastic chemotherapies. Thus, the study group revised the classification criteria in 2015; HBV carriers developing acute hepatitis exacerbation were classified into asymptomatic or inactive HBV carriers and patients with previously resolved HBV infection, and both groups were further sub-classified into those receiving immunosuppressive therapies and/or antineoplastic chemotherapies and those without such drugs exposure.

Aim Sorafenib is the recommended standard of care for advanced hepatocellular carcinoma (HCC) patients. However, hepatic arterial infusion chemotherapy (HAIC) is a treatment option in Asia. We recently developed the ‘assessment for continuous treatment with HAIC’ (ACTH) score to guide decision-making for continuous HAIC treatment. The purpose of this study was to validate the utility of the ACTH score in a dedicated cohort. Methods One-hundred and thirty-one advanced HCC patients were enrolled in this study (90 in the training group and 41 in the validation group). The point score (range: 0–3) was calculated as follows: Child-Pugh score before HAIC (A = 0, B = 1), alpha-fetoprotein (AFP) response (yes = 0, no = 1), and des-gamma-carboxy prothrombin (DCP) response (yes = 0, no = 1). AFP and DCP responses were assessed 2 weeks after HAIC induction; a positive response was defined as a reduction of ≥20% from the baseline. Results The DCP response in the validation group was significantly associated with treatment response, and the median survival time (MST) was longer in patients with an ACTH score ≤1 (15.9 months) than in those with a score ≥2 (7.0 months; p = 0.002). Survival in all patients showed significant stratification according to the ACTH score; the MSTs associated with scores of 0, 1, 2, and 3 points were 21.7, 14.4, 9.5, and 3.8 months, respectively. Conclusions The ACTH score can aid in the therapeutic assessment and continued treatment planning of HCC patients receiving HAIC.

Aim Insulin resistance (IR) increases during the early stages of hepatitis C virus (HCV)-related chronic liver disease and is a sign of poor prognosis as well as a risk factor for hepatic fibrosis and hepatocellular carcinoma. We aimed to determine the factors affecting IR in HCV-related chronic liver disease. Methods We retrospectively examined 71 patients with HCV-related chronic liver disease and analyzed various parameters, including amino acids, as possible predictors of IR. IR was assessed using the Homeostasis Model of Assessment – Insulin Resistance (HOMA-IR). Amino acids were assayed by examining branched-chain amino acids (BCAA), tyrosine level, and the ratio of BCAA to tyrosine level (BTR). Results HOMA-IR was significantly correlated with body mass index, platelet count, prothrombin time, hemoglobin, total bilirubin, total protein, albumin, total cholesterol, fasting glucose, BTR (r = −0.46, P = 0.0001) and tyrosine (r = 0.55, P

Aim To overcome current limitations of therapy for liver diseases, cell-based therapies using mesenchymal stem cells (MSC) have been attempted through basic and clinical approaches. Oxidative stress is a crucial factor in hepatology, and reactive oxygen species (ROS) are well-established molecules responsible for its deleterious effects. The antioxidant properties of MSC were recently demonstrated, and therefore we examined the antioxidant activity of canine MSC (cMSC), their effects on isolated hepatocytes in vitro and their curative potential against thioacetamide (TAA)-induced liver injury in vivo. Methods To evaluate the ability of cMSC to challenge oxidative stress, cell viability, cytotoxicity and ROS were measured in cultured cMSC treated with TAA. Also, cMSC were co-cultured with hepatocytes in the same injury condition, and the ROS level was measured exclusively in hepatocytes. Finally, to verify the curative potential of cMSC, 2.0 × 106 cells or phosphate-buffered saline were injected systemically in non-obese diabetic/severe combined immunodeficiency mice that received TAA injections twice a week for 13 weeks. We then evaluated histological parameters, serum injury markers and redox homeostasis. Results cMSC overcame TAA-induced oxidative stress in vitro, as shown by increased viability and lower cytotoxicity and ROS levels. Moreover, hepatocytes co-cultured with cMSC also showed decreased cellular ROS. The in vivo study showed that mice treated with cMSC presented with an ameliorated histological pattern, suppressed fibrosis, lower serum injury marker levels and better oxidative parameters. Conclusion We concluded that cMSC injection reduce TAA-induced liver injury through antioxidant activities and hepatoprotective effects, showing a curative potential in liver diseases.

We studied the comprehensive DNA methylation status in the naturally derived gastric adenocarcinoma cell line SNU-719, which was infected with the Epstein-Barr virus (EBV) by methylated CpG island recovery on chip assay. To identify genes specifically methylated in EBV-associated gastric carcinomas (EBVaGC), we focused on seven genes, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1, based on the results of methylated CpG island recovery on chip assay. We confirmed DNA methylation of the genes by methylation-specific PCR and bisulfite sequencing in SNU-719. The expression of the genes, except for BCL7A, was upregulated by a combination of 5-Aza-2'-deoxycytidine and trichostatin A treatment in SNU-719. After the treatment, unmethylated DNA became detectable in all seven genes by methylation-specific PCR. We verified DNA methylation of the genes in 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV-negative patients who were controls. The methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGC than in EBV-negative gastric carcinoma. We identified seven genes with promoter regions that were specifically methylated in EBVaGC. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor-associated antigens and help to develop and maintain EBVaGC.

Aim Although it is an important treatment challenge to treat ascites with diuretic therapy, no objective markers have been established to assess improvement of ascites. However, change in bodyweight has been used as a marker of change in ascites volume. Thus, we evaluated the relationship between changes in bodyweight and changes in ascites volume in liver cirrhosis patients with ascites. Methods We calculated ascites volume in patients using the simple 5-point method by conventional computed tomography and conducted a correlation analysis between changes in bodyweight and changes in ascites volume as a part of our double-blind phase 3 trial of tolvaptan. Result Change in bodyweight (x-axis) was correlated with change in ascites volume (y-axis) in all included patients (r = 0.52). A strong correlation were observed between the changes in patients without lower limb edema (r = 0.61). These correlations between the changes were expressed by the following linear regression equations: y = −0.102 + 0.206x or y = −0.033 + 0.292x, respectively. Proportions of change in ascites volume to change in bodyweight were estimated to be nearly 30%. Therefore, bodyweight reduction was confirmed to lead to improvement in ascites. Conclusion Change in bodyweight can be an objective marker to assess improvement of hepatic edema in the short-term diuretic therapy in everyday clinical practice. Decrease in ascites volume was estimated to account for nearly 30% of bodyweight reduction.

Aim We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anticancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC). Methods We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors. Results The 1-, 2- and 3-year cumulative survival rates were 36.4%, 18.2% and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin of 190 mg/dL or more (MST, 12.0 months) were significantly better than those of patients who had serum transferrin of less than 190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin of 190 mg/dL or more (hazard ratio [HR], 0.282; 95% confidence interval [CI], 0.132–0.603; P = 0.001) and Child–Pugh score B (HR, 1.956; 95% CI, 1.034–3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P

Hepatic edema is manifested by ascites, lower limbedema and intolerable symptoms. Some patients insuffi-ciently respond to the conventional diuretic therapy. There-fore, a novel therapeutic option is required. We conducted aphase 3 study to confirm therapeutic effect of tolvaptan onhepatic edema associated with liver cirrhosis.

Aim Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7-day, multicenter, double-blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema. Methods Liver cirrhosis patients with inadequate diuretic response despite having received a conventional diuretic therapy were enrolled in the trial. Participants were stratified randomly to four groups receiving tolvaptan at 7.5, 15 or 30 mg/day, or placebo as an add-on to conventional diuretics once daily for 7 days. Changes in bodyweight and abdominal circumference were analyzed. Serum sodium concentrations were measured. Safety assessment was performed. Results Tolvaptan at 7.5–30 mg/day reduced bodyweight and abdominal circumference compared with placebo. Serum sodium concentrations remained within the normal range in all tolvaptan groups. Serious adverse events were not observed, and most common adverse event was thirst. Tolvaptan at 7.5 mg/day showed the maximum change in bodyweight and abdominal circumference together with preferable tolerability. Conclusion Tolvaptan at 7.5 mg/day was considered the optimal dose in liver cirrhosis patients with hepatic edema who showed inadequate response to conventional diuretics.

The frequencies of DNA methylation of certain tumor-related genes are higher in Epstein-Barr virus (EBV)-associated gastric carcinomas than in EBV-negative gastric carcinomas. EBV-associated gastric carcinomas have distinct clinicopathological features; however, there are no case-control studies comparing methylation frequency between EBV-associated gastric carcinomas and controls that have been adjusted according to the clinicopathological features of EBV-associated gastric carcinomas. This study evaluated 25 EBV-associated gastric carcinomas that were positive for EBV-encoded small RNA 1 (EBER-1) by in situ hybridization and 50 EBV-negative gastric carcinomas that were matched with the EBV-associated gastric carcinomas by age, sex, histology, depth of tumor invasion, and stage. Methylation status of 16 loci associated with tumor-related genes was analyzed by methylation-specific polymerase chain reaction (PCR) to identify genes in which DNA methylation specifically occurred in EBV-associated gastric carcinomas. Methylation frequencies of 12 of the 16 genes were higher in EBV-associated gastric carcinomas than in EBV-negative controls, and the frequency of methylation of 6 specific loci (MINT2, MINT31, p14, p16, p73, and RUNX3) was significantly higher in EBV-associated gastric carcinomas than in EBV-negative controls. There were no significant differences in the methylation frequencies of the other genes. The mean methylation index in EBV-associated gastric carcinomas was significantly higher than that in EBV-negative controls. DNA methylation of tumor suppressor genes that regulate the cell cycle and apoptosis specifically occurred in EBV-associated gastric carcinomas. Aberrant DNA methylation might lead to the development and progression of EBV-associated gastric carcinoma.

Aim Problems in patients with minimal hepatic encephalopathy (MHE) include episodes such as falls and deficient driving skills, without any recognition of neurophysiological dysfunction. Patients with MHE are also more likely to develop overt hepatic encephalopathy. However, there is not yet any interventional strategy for MHE involving nutritional management. We conducted a preliminary study to investigate the proportion of positive MHE and the effects of nutritional management on MHE. Methods Patients with viral liver cirrhosis and abnormal neuropsychological tests were included. Nutritional consultations were conducted periodically by a dietitian, who recommended 30–35 kcal with 1.0–1.5 g of protein/kg of ideal bodyweight/day. The primary end-point was to evaluate the proportion of patients who recovered from MHE. The secondary end-point was to evaluate the improvement in the patients' quality of life (QOL). Results Thirty-two (30.1%) of 106 patients were diagnosed with MHE. Nineteen patients were enrolled in the study. Eleven of 19 patients became non-MHE after 4 weeks, and 13 of 19 patients (68.4%, P

Aim: One of the prohibiting factors in achieving complete small bowel capsule endoscopy is slow gastric transit of the capsule. The present study retrospectively investigated the success rate of, and the time required for, transnasal endoscope-assisted capsule placement to assess its clinical utility. Methods: In 24 of 27 patients who underwent capsule placement assisted by a transnasal endoscope, the capsule was successfully transported to and released in the duodenum (capsule placement group). For each patient in the capsule placement group, three age- and sex-matched patients who underwent conventional capsule endoscopy were assigned as controls (n = 72). Gastric transit time, small bowel transit time, and rate of capsule arrival at the cecum within 8 h were compared between the two patient groups. Results: Among the 27 patients in whom capsule placement was carried out, the capsule was successfully placed in the duodenum in 24 patients (88.9% success rate). In the capsule placement group, gastric transit time was significantly shorter (10.5 vs 46.2 min, P = 0.0021), small bowel transit time was significantly longer (354.7 vs 301.3 min, P = 0.0134), and completion rate (capsule arrival at the cecum within 8 h) was significantly higher (83.3 vs 61.1%, P = 0.0455) than in the control group. There were no procedural accidents associated with capsule placement. Conclusion: Transnasal endoscope-assisted capsule placement appears to be a safe and reliable procedure, achieving complete small bowel capsule endoscopy, and is considered clinically useful.

Aim: The Japanese Nutritional Study Group for Liver Cirrhosis (JNUS) was assembled in 2008 with the support of a Health Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare of Japan. The goal of the study group was to propose new nutritional guidelines for Japanese patients with liver cirrhosis (LC), with the aim of preventing hepatocellular carcinoma. Methods: Between 2008 and 2010, the member investigators of JNUS conducted various clinical and experimental studies on nutrition on LC. These included anthropometric studies, a questionnaire study on daily nutrient intake, clinical trials, experimental studies using animal models, re-evaluation of previous publications and patient education. Over this 3-year period, the group members regularly discussed the nutritional issues related to LC, and a proposal was finally produced. Results: Based on the results of JNUS projects and discussions among the members, general recommendations were made on how Japanese patients with LC should be managed nutritionally. These recommendations were proposed with a specific regard to the prevention of hepatocarcinogenesis. Conclusion: The new JNUS guidelines on nutritional management for Japanese patients with LC will be useful for the actual nutritional management of patients with LC. The JNUS members hope that these guidelines will form the basis for future discussions and provide some direction in nutritional studies in the field of hepatology.

Aim: Diabetes mellitus (DM) has been reported to worsen the long-term prognosis of cirrhotic patients, and many studies have reported that DM is an independent risk factor for hepatocellular carcinoma. However, an accurate diagnosis of DM is sometimes difficult in cirrhotic patients. Recently, a novel non-invasive 13C-glucose breath test has been reported to be useful for diagnosing insulin resistance in non-cirrhotic patients. The aim of this study was to evaluate the efficacy of this tool for the identification of DM in cirrhotic patients. Methods: Thirty eight cirrhotic patients with normal fasting serum glucose and hemoglobin A1c levels underwent the 13C-glucose breath test and the oral glucose tolerance test. Blood and breath samples were collected at baseline and at 30, 60 and 120 min after ingestion of 100 mg 13C-labeled glucose and 75 g glucose. Results: There was a strong correlation between the change in the concentrations at 2 h for the measured 13C-glucose breath test (2h-BT) and the 2 h plasma glucose level (r = −0.60, P

The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Study Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements".

We have previously reported the efficacy and safety of autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients without hepatocellular carcinoma in a multicenter clinical trial. However, since liver cirrhosis is highly oncogenic, evaluation of the effects of ABMi on the mechanisms of hepatocarcinogenesis is of great importance. Therefore, frequent ABMi was performed in hepatocarcinogenic mice, and its effects on hepatocarcinogenesis were analyzed. The N-nitrosodiethylamine (DEN)/green fluorescent protein (GFP)-carbon tetrachloride (CCl(4) ) model was developed by administering DEN once, followed by repeated administration of CCl(4) intraperitoneally as for the control group. In the administration (ABMi) group, GFP-positive bone marrow cells were infused through a tail vein. The kinetics of hepatocarcinogenesis were evaluated histologically 4.5 months after DEN treatment. At 4.5 months, there was significantly lower incidence of foci and tumors in the ABMi group, and they were smaller in number, while their size was almost equal. No GFP-positive tumors were found in ABMi livers. Moreover, ABMi livers showed significantly reduced liver fibrosis, consistent with significantly lower 8-hydroxy-2'-deoxyguanosine levels, higher superoxide dismutase activity, and increased nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2. These results demonstrate that frequent ABMi might contribute to suppressed tumor initiation during stages of hepatocarcinogenesis, consistent with improvements in liver fibrosis and stabilization of redox homeostasis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The most common problem associated with HCC is a high risk of intrahepatic recurrence despite radical treatment, and in many patients, this recurrence has fatal consequences. For patients with advanced-stage HCC according to the Barcelona Clinic Liver Cancer staging system, the multikinase inhibitor sorafenib is the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is the recommended treatment in Japan for patients with intermediate-stage or advanced-stage HCC. In this review, we describe the use of HAIC for advanced HCC. Furthermore, we demonstrate an alternative therapy for HCC, the iron chelator deferoxamine, and discuss future therapeutic possibilities.

AIM This study investigated whether splenectomy is of significance in non-alcoholic steatohepatitis (NASH). METHODS Five-week-old Wistar rats were fed a choline-deficient diet for 8 weeks to create a NASH model. A sham-operation or splenectomy was then performed, and rats were killed 4 weeks later. RESULTS Liver fibrosis and liver preneoplastic lesions were significantly reduced in the splenectomy group compared to the sham-operation group, and α-smooth muscle actin (SMA) expression was significantly inhibited (liver fibrosis area: sham 8.63 ± 4.09%, splenectomy 5.45 ± 3.69%, P

Background/Aim: A European randomized trial showed biochemical effects of 6-month treatment with Stronger Neo-Minophagen C™ (SNMC), a glycyrrhizin-containing preparation, in patients with chronic hepatitis C, but its underlying mechanisms remain elusive. We reported previously that SNMC exhibits an anti-oxidative effect in hepatitis C virus (HCV) transgenic mice that develop marked hepatic steatosis with mitochondrial injury under iron overloading. Hepatic steatosis and iron overload are oxidative stress-associated pathophysiological features in chronic hepatitis C. The aim of this study was to investigate whether long-term treatment with SNMC could prevent the development of hepatic steatosis in iron-overloaded HCV transgenic mice. Methods: C57BL/6 transgenic mice expressing the HCV polyprotein were fed an excess iron diet concomitantly with intraperitoneal injection of saline, SNMC, or seven-fold-concentrated SNMC thrice weekly for 6 months. Results: Stronger Neo-Minophagen C™ inhibited the development of hepatic steatosis in a dose-dependent manner without affecting hepatic iron content, attenuated ultrastructural alterations of mitochondria of the liver, activated mitochondrial β-oxidation with increased expression of carnitine palmitoyl transferase I and decreased the production of reactive oxygen species in the liver in iron-overloaded transgenic mice. However, SNMC hardly affected the unfolded protein response, which post-transcriptionally activates sterol regulatory element-binding protein 1, a transcription factor involved in lipid synthesis, even though we reported previously the activation of the unfolded protein response in the same iron-overloaded transgenic mice. Conclusions: These results suggest that SNMC prevents hepatic steatosis possibly by protecting mitochondria against oxidative stress induced by HCV proteins and iron overload.

Background: There is no consensus on the choice of either unilateral or bilateral drainage in stent placement for patients with unresectable hilar biliary obstruction. The aim of the present study was to clarify which drainage method is superior. Methods: We retrospectively reviewed 82 patients with hilar biliary obstruction who underwent metallic stenting. These patients were divided into a unilateral drainage group (Uni group) and a bilateral drainage group (Bi group). Results: There was no significant difference between the groups in median survival time, median stent patency period, and median complication-free survival time. The most frequent complication was stent obstruction, followed by cholangitis. Liver abscess was found at a higher frequency in the Bi group (17.6%) than in the Uni group (1.5%) (P = 0.0266). There was no significant difference between the groups in the occurrence of two or more complications (P = 0.247), life-threatening severe complications (P = 0.0577), and stent obstruction by sludge (P = 0.0912). Conclusion: When compared with bilateral biliary drainage, unilateral biliary drainage is associated with a lower incidence of liver abscess as well as a comparable outcome of stent patency time and complication-free survival. We therefore propose that hilar biliary obstruction can be treated first by unilateral drainage with a metallic stent and by bilateral drainage only in patients who develop cholangitis in the contralateral biliary tree.

Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I–II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56+ cells and CD56−CD3+ T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase–polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment. (Cancer Sci 2010; 101: 2333–2340)

Aim: A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched-chain amino acid (BCAA)-enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75-g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non-protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early-stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA-enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.