Search

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that mainly injures the hepatocytes. The autoimmune disease might be involved in its aetiology, but this remains to be confirmed. Recently epidemiological studies of AIH in Asia have been broadly conducted, revealing characteristics and management of AIH patients in Asia. In East Asia, most AIH patients are type 1, and type 2 AIH is very rare. However, type 2 AIH in South Asia is as frequent as in Europe and the USA. HLA‐DR4 is associated with the characteristics of type 1 AIH in East Asia, whereas HLA‐DR3 occurs in AIH patients from South Asia. AIH prevalence worldwide is increasing, and several studies have reported a prevalence of 19.44, 22.80 and 12.99 per 100 000 people in Europe, the USA and Asia respectively. A meta‐analysis of studies on AIH showed similar annual incidence rates for all regions, with 1.31, 1.37 and 1.00 per 100 000 people in Asia, Europe and the USA respectively. The increase in the rates could be attributable to the increased awareness of disease concepts and diagnosis. In South Asia, most cases were diagnosed as AIH only after having progressed to cirrhosis, which may cause a higher mortality rate in South Asia than in East Asia. Therefore, the early diagnosis and treatment of AIH patients can improve the current situation in Asia. [ABSTRACT FROM AUTHOR]

Background and Aim: Obesity, insulin resistance, and metabolic alterations increase the risk of colorectal cancer and adenoma (CRA). Non‐alcoholic fatty liver disease (NAFLD) or pancreatic disease (NAFPD) shares many risk factors with CRA that may have significant roles in its development; however, the relationship between CRA and NAFLD/NAFPD remains unclear. Methods: This cross‐sectional study recruited 712 eligible participants without current drinking who had undergone total colonoscopy as part of a health checkup. These participants were classified into a CRA group (n = 236) and a control group (n = 439), which consisted of individuals without CRA and a history of polyp resection. NAFLD and NAFPD were diagnosed based on abdominal ultrasonography findings. Results: Non‐alcoholic fatty liver disease was observed more frequently in individuals with CRA than in the control group (55.9% vs 41.6%, P < 0.01). There was no significant association between NAFPD and CRA; however, serum pancreatic amylase (P‐amylase) levels were significantly lower in individuals with CRA. Although NAFLD was one of the factors increasing the presence of CRA (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.07–2.10), low P‐amylase levels were significantly associated with the presence of CRA (OR, 1.73; 95% CI, 1.04–2.88) independent of age, sex, current smoking, obesity, metabolic alterations including insulin resistance, and NAFLD. Conclusions: Low serum P‐amylase levels were a possible independent risk factor for CRA in the present study. The latent pancreatic exocrine–endocrine–gut relationship was considered a novel pathway involved in obesity‐related CRA development, in non‐alcoholic individuals. [ABSTRACT FROM AUTHOR]

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice. [ABSTRACT FROM AUTHOR]

Granulocyte and monocyte adsorptive apheresis (GMA), an effective therapy for inflammatory disorders, exerts an anti‐inflammatory influence by utilizing the biological reaction between blood and cellulose acetate (CA) beads, which are the carriers of the GMA column. Although the biological reaction has an optimum temperature, blood contacts the CA beads below body temperature as GMA is performed in an extracorporeal circulation system. We investigated various soluble factors in blood treated with CA beads at 25°C and 37°C. Here, the optimal temperature for IL‐1 receptor antagonist (IL‐1ra) release induced by CA beads was 37°C, and IL‐6 production from monocytic cells was inhibited by the addition of plasma prepared from the CA bead‐treated blood at 37°C, rather than at 25°C. These results indicated that physiological heating of the apheresis carrier augmented the anti‐inflammatory reaction in vitro. Thus, heating during GMA may be a new approach for augmenting clinical efficacy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study examines the removal of nitrogen from nitrate, which accumulates in the anammox process, during the heterotrophic denitrification (HD) reaction using organic compounds that were originally contained in the influent as electron donors. The experimental system comprises a single partial‐nitritation/anammox (PNA) reactor and HD reactor for biological oxygen demand (BOD) reduction that is placed in series before the PNA reactor. A portion of the effluent from the PNA reactor was allowed to flow back to the HD reactor. The nitrate concentration in the effluent from the PNA reactor reduced as the recirculation ratio increased and the maximum nitrogen removal efficiency (NRE) was optimized at a hydraulic retention time (HRT) of 3.0 hours in the HD reactor out of a total HRT of 36 hours at 4 backflow/influent, demonstrating an NRE of 95.4% that represented an enhancement of 1.24 times the NRE without recirculation in the flow path. [ABSTRACT FROM AUTHOR]

Background and Aim: Obesity affects the gut microbiome, which in turn increases the risk for colorectal cancer. Several studies have shown the mechanisms by which some bacteria may influence the development of colorectal cancer; however, gut microbiome characteristics in obese patients with colorectal cancer remain unclear. Therefore, this study evaluated their gut microbiome profile and its relationship with metabolic markers. Methods: The study assessed fecal samples from 36 consecutive patients with colorectal cancer and 38 controls without colorectal cancer. To identify microbiotic variations between patients with colorectal cancer and controls, as well as between nonobese and obese individuals, 16S rRNA gene amplicon sequencing was performed. Results: Principal coordinate analysis showed significant differences in the overall structure of the microbiome among the study groups. The α‐diversity, assessed by the Chao1 index or Shannon index, was higher in patients with colorectal cancer versus controls. The relative abundance of the genera Enterococcus, Capnocytophaga, and Polaribacter was significantly altered in obese patients with colorectal cancer, whose serum low‐density lipoprotein concentrations were positively correlated with the abundance of the genus Enterococcus; among the most abundant species was Enterococcus faecalis, observed at lower levels in obese versus nonobese patients. Conclusions: This study demonstrated several compositional alterations of the gut microbiome in patients with colorectal cancer and showed that a reduced presence of E. faecalis may be associated with obesity‐related colorectal cancer development. The gut microbiome may provide novel insights into the potential mechanisms in obesity‐related colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Aim: To clarify the outcome and predictive factors in patients with acute liver failure (ALF) awaiting deceased donor liver transplantation (DDLT) in Japan. Methods: Of the DDLT candidates in Japan between 2007 and 2016, 264 adult patients with ALF were retrospectively enrolled in this study. Factors associated with DDLT and waiting‐list mortality were assessed using the Cox proportional hazard model. The DDLT and transplant‐free survival probabilities were evaluated using Kaplan–Meier analysis and the log–rank test. Results: The waiting‐list registration year after the Transplant Law revision in 2010 was a significant factor associated with DDLT. The adjusted hazard ratio indicated that DDLT probability after 2010 was four times higher than that before, and the 28‐day cumulative DDLT probability was more than 35%. The median survival time of the entire cohort was 40 days. Multivariate analysis identified the following three factors associated with waiting‐list mortality: age, coma grade, and international normalized ratio. The transplant‐free survival probabilities were significantly stratified by the number of risks, and patients with all three risks showed extremely poor short‐term prognosis (median survival time = 23 days). Conclusions: The DDLT probability of ALF patients increased after the law revision in 2010; however, patients at high risk of short‐term waiting‐list mortality might need emergent living donor transplantation. [ABSTRACT FROM AUTHOR]

Aim: The combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for the treatment of various hepatitis C virus (HCV) genotypes across many countries. This article presents an integrated analysis of three prospective phase II/III trials in the Asia‐Pacific region to evaluate the efficacy and safety of 12 weeks of LDV/SOF in HCV genotype 2 patients without cirrhosis or with compensated cirrhosis. Methods: A total of 200 patients were included in the integrated analysis. The primary end‐point was the rate of sustained virologic response for 12 weeks after the end of therapy (SVR12), analyzed by fibrosis stage, treatment history, HCV genotype subtype, and presence of baseline resistance‐associated substitutions (RAS). Safety was evaluated by adverse events and laboratory abnormalities. Results: Twelve weeks of treatment with LDV/SOF was associated with high SVR12 rates (overall 98%) in patients with genotype 2 HCV, irrespective of fibrosis stage, treatment history, genotype 2 subtype, and presence of baseline non‐structural protein 5A resistance‐associated substitution (NS5A RAS), and LDV/SOF was well tolerated. Conclusions: Twelve weeks of treatment with LDV/SOF provides a highly effective and safe treatment for patients with genotype 2 HCV, including those with advanced fibrosis. As a ribavirin‐free and protease inhibitor‐free regimen with minimal on‐treatment monitoring requirements, LDV/SOF can potentially play a crucial role in achieving the WHO's goal of HCV elimination. [ABSTRACT FROM AUTHOR]

Background and objectives: Although HLA‐eliminated platelets can facilitate transfusions to patients possessing HLA antibodies, no such products are currently available commercially perhaps because the platelet collection rate is not yet economically viable. We have improved this process' efficiency by employing a hollow‐fibre system at the last step of the production process after an acid and a reaction buffer have been washed out conventionally by centrifugation. Materials and methods: HLA‐eliminated platelets were prepared via four distinct steps: chilled on ice, treated with an acid solution, diluted and finally washed using the hollow‐fibre system. The efficiency of this platelet recovery process was determined. The resulting products' platelet characteristics, including a capacity for HLA expression, were evaluated in vitro and compared in detail to their corresponding originals. Results: The average efficiency of platelet recovery was 91%. Although the expression levels of CD62P, a molecular marker for platelet activation, were approximately threefold higher on new platelets than on the original platelets, their HLA expression levels were lower. The phagocytosis assay, with monoclonal antibodies and cognate HLA antibody‐containing sera, suggested that HLA‐ABC molecules on the cell surface were sufficiently removed. The platelet functions, including the agonist‐induced aggregability and adherence/aggregability of the collagen‐coated plates under certain conditions, were conserved and not significantly different from the original ones. Conclusion: We propose a novel preparation system for producing HLA‐eliminated platelets without centrifugation, which ensures a highly efficient, and therefore, much more economical method of platelet recovery that also retains their key functionality. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to investigate comprehensively, the risk factors for underweight in cross‐sectional study in the general population of Japan. Methods: The survey population was the general population of individuals aged >40 years in Takahata town, Japan in 2005. A postal survey in the form of a self‐administered questionnaire was distributed, and 6084 individuals were entered into the final statistical analysis. The self‐administered questionnaire contained items regarding lifestyle, oral health status, socio‐economic status and dietary intake. To examine the independent relationships between an underweight status and several parameters, a multivariate logistic regression analysis was used to estimate adjusted odds ratios (ORs). Results: The number of teeth, age, alcohol consumption, hypertension, spousal status, smoking habit, appetite, body weight at 20 years of age, habit of going out and physical activity were independently associated with an underweight status compared with the normal weight group. Individuals with fewer than 10 teeth were especially more likely to be underweight than individuals with more than 20 teeth (OR = 1.956, 95% CI = 1.261‐3.035). Conclusion: This study showed an independent association between the number of teeth and an underweight status, indicating that fewer teeth can increase the risk of being underweight. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long‐term studies have examined the development of HCC in HBV/B‐infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B‐ or HBV/C‐infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)‐positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB‐4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20‐year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B‐infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes. [ABSTRACT FROM AUTHOR]

Aim: In order to know the present status of drug‐induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. Methods: Drug‐induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. Results: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug‐induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty‐three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)‐Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". Conclusions: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW‐Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Japanese patients with chronic hepatitis C virus (HCV) genotype 2 infection have high rates of sustained virological response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin, which was the standard of care at the time this study was undertaken. We assessed the efficacy of 12 weeks of treatment with a ribavirin‐free regimen of ledipasvir‐sofosbuvir. Methods: In an open‐label, Phase 3 trial we enrolled Japanese patients with chronic HCV genotype 2 infection, with or without compensated cirrhosis. In Cohort 1, participants were randomized 1:1 to receive ledipasvir‐sofosbuvir (n = 106) or sofosbuvir + ribavirin (n = 108) for 12 weeks. In Cohort 2, 25 ribavirin‐intolerant or ‐ineligible patients received ledipasvir‐sofosbuvir for 12 weeks. The primary endpoint was SVR 12 weeks after therapy (SVR12). In Cohort 1 non‐inferiority was assessed with a prespecified margin of 10%. Results: One‐third (33%) of patients were treatment experienced, and 14% had cirrhosis. In Cohort 1, SVR12 rates were 96% (95% CI, 91% to 99%) with ledipasvir‐sofosbuvir and 95% (95% CI, 90% to 98%) with sofosbuvir plus ribavirin, thus achieving non‐inferiority. Among ribavirin‐intolerant/ineligible patients in Cohort 2, SVR12 was 96% (95% CI, 80% to 100%) with ledipasvir‐sofosbuvir. Overall, the most common adverse events were nasopharyngitis, anaemia, and headache; anaemia was only observed in patients receiving ribavirin. The percentage of patients who discontinued treatment because of an adverse event was low (1%). Conclusions: Among Japanese patients with HCV genotype 2, 12 weeks of treatment with ledipasvir‐sofosbuvir resulted in high rates of SVR12 that were non‐inferior to sofosbuvir + ribavirin. [ABSTRACT FROM AUTHOR]

Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart-type fatty acid-binding protein (H-FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community-based annual health check. Serum levels of BNP and H-FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H-FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H-FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H-FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H-FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure. [ABSTRACT FROM AUTHOR]

Activation of blood cells during hemodialysis is considered to be a significant determinant of biocompatibility of the hemodialysis membrane because it may affect patient health adversely through microvascular inflammation and oxidative stress. This study found very different cell activation among various polysulfone (PSf) hemodialysis membranes. For example, CX‐U, a conventional PSf membrane, induced marked adhesion of platelets to its surface and increased surface expression of activated CD11b and production of reactive oxygen species (ROS) by neutrophils; while NV‐U, a hydrophilic polymer‐immobilized PSf membrane, caused little platelet adhesion and slight CD11b expression and ROS production by neutrophils. Analysis of the molecular mechanisms of the above phenomena on CX‐U and NV‐U indicated that anti‐integrin GPIIb/IIIa antibody blocked platelet adhesion, and that the combination of anti‐CD11b (integrin α subunit of Mac‐1) and anti‐integrin αvβ3 antibodies blocked ROS production by neutrophils. Plasma‐derived fibrinogen, a major ligand of GPIIb/IIIa, Mac‐1, and αvβ3 on membranes, was thus analyzed and found to be more adsorbed to CX‐U than to NV‐U. Moreover, comparison between five PSf membranes showed that the number of adherent platelets and neutrophil ROS production increased with increasing fibrinogen adsorption. These results suggested that fibrinogen, adsorbed on membranes, induced GPIIb/IIIa‐mediated platelet activation and Mac‐1/αvβ3‐mediated neutrophil activation, depending on the amount of adsorption. In conclusion, the use of biocompatible membranes like NV‐U, which show lower adsorption of fibrinogen, is expected to reduce hemodialysis‐induced inflammation and oxidative stress by minimizing cell activation. [ABSTRACT FROM AUTHOR]

Abstract: Circulating levels of soluble intercellular adhesion molecule‐1 (sICAM‐1) and vascular adhesion molecule‐1 (sVCAM‐1) are elevated in patients with inflammatory bowel disease. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis (GMA). We investigated the effect of CA beads on sICAM‐1 and sVCAM‐1 plasma concentrations in vitro. Because GM adsorption to CA beads increased with a rise in the incubation temperature in our previous study, peripheral blood was incubated with and without CA beads at 5, 25, 37, or 43 °C and plasma sICAM‐1 and sVCAM‐1 was measured. The sICAM‐1 and sVCAM‐1 concentrations in samples incubated with CA beads were significantly lower than those without CA beads at all four temperatures. However, no significant differences were observed both sICAM‐1 and sVCAM‐1 plasma levels at the four different temperatures after incubation with CA beads. These results suggest that independent of incubation temperature, sICAM‐1 and sVCAM‐1 are likely to adsorb CA beads. These molecules may be a new index for predicting the therapeutic effects of GMA. [ABSTRACT FROM AUTHOR]

Aim Aim: To clarify the survival and prognostic factors in patients with Child-Turcotte-Pugh class C (CTP-C) cirrhosis. Methods From all candidates for deceased donor liver transplantation in Japan between 2007 and 2015, 1014 adult patients with CTP-C cirrhosis were retrospectively enrolled in this study. The hazard ratio (HR) of factors associated with mortality was estimated by the Cox proportional hazard model. The survival probabilities were evaluated by Kaplan-Meier analysis and the log-rank test. Results Median survival time of the entire cohort was 475 days. Univariate analysis identified age, CTP, Model for End-Stage Liver Disease (MELD) score, and primary biliary cholangitis (PBC) as significant variables associated with mortality and hepatitis B virus (HBV) infection as a close-to-significant variable. Multivariate analysis revealed that age-adjusted mortality risk increased by 59% and 12% per 1 score step up in CTP and MELD scores, respectively. The HRs for HBV infection and PBC were significant after adjustment for age and CTP score, and they showed a 26% lower risk and an 83% higher risk than hepatitis C virus (HCV) infection, respectively. After adjustment for age and MELD score, the HR was also significant for HBV infection, but lost statistical significance for PBC. The survival curves were well stratified by both CTP or MELD score and revealed significant difference in both HBV infection and PBC as compared to HCV infection. Conclusions In patients with CTP-C cirrhosis, CTP and MELD scores could well stratify the patients' survival, and HBV infection and PBC as etiologies have an impact on survival. [ABSTRACT FROM AUTHOR]

Granulocyte and monocyte (GM) adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including inflammatory bowel disease (IBD). During GMA, the blood of a patient with IBD passes through a column to contact cellulose acetate (CA) beads at a temperature below body temperature, likely close to room temperature. Here we investigated the effect of temperature on GM adsorption to CA beads in vitro. We incubated peripheral blood with and without CA beads at 5°C, 25°C, 37°C, and 43°C and calculated the ratios of adsorbed GMs. The ratios of adsorbed GMs increased as the temperature was raised. Additionally, we measured complement activation fragment concentrations. C3a and C5a concentrations also increased as the temperature was raised, and C5a concentrations had a positive correlation with the ratios of adsorbed GMs. These results suggest that warming the column during GMA might increase GM adsorption to CA beads, thereby enhancing the clinical efficacy of GMA. [ABSTRACT FROM AUTHOR]

The liver is innervated by both the sympathetic and the parasympathetic nerve systems. These nerves are derived from the splanchnic and vagal nerves that surround the portal vein, hepatic artery, and bile duct. The afferent fiber delivers information regarding osmolality, glucose level, and lipid level in the portal vein to the central nervous system (CNS). In contrast, the efferent fiber is crucial in the regulation of metabolism, blood flow, and bile secretion. Furthermore, liver innervation has been associated with hepatic fibrosis, regeneration, and circadian rhythm. Knowledge of these mechanisms can be applied for potential liver disease treatment. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-23, which is released by activated monocytes and neutrophils, promotes production of high levels of IL-17 by T-helper 17 cells. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis using Adacolumn. Contact between blood and CA beads induces cytokine release; however, their inflammatory effects on IL-23 release are unclear. We aimed to clarify the effect of CA beads on IL-23 release in vitro. We incubated peripheral blood with and without CA beads and measured IL-23. Compared to blood samples incubated without CA beads, blood samples incubated with CA beads had significantly decreased amounts of IL-23. In conclusion, CA beads inhibited IL-23 release from adsorbed GMs. The biological effects of this decrease in IL-23 release during GM adsorption to CA beads need further clarification. [ABSTRACT FROM AUTHOR]

The number of cancer survivors is increasing; however, optimal health management of cancer survivors remains unclear due to limited knowledge. To elucidate the risk of non-communicable diseases, and the effect of lifestyle habits on risk of non-communicable diseases, we compared cancer survivors and those who never had cancer (non-cancer controls) using a population-based prospective cohort study. The baseline survey of 2292 participants was carried out from 2004 to 2006, and the follow-up survey of 2124 participants was carried out in 2011. We compared the baseline characteristics and the risk of non-communicable diseases between cancer survivors and non-cancer controls. Analyzed participants included 124 cancer survivors (men / women, 57 / 67), and 2168 non-cancer controls (939 / 1229). Several lifestyle factors and nutritional intake significantly differed between survivors and non-cancer controls, although smoking status did not differ between the groups (P = 0.30). Univariate logistic regression analysis showed increased risk of death (odds ratio [OR], 3.64; 95% confidence interval [CI], 2.19- 6.05) and heart disease (OR, 2.60; 95% CI, 1.06-6.39) in cancer survivors. Increased risk of heart disease was also significant (OR, 2.95; 95% CI, 1.05-8.26; P = 0.04) in the multivariate analysis of the smoking-related cancer subgroup. Current smoking significantly increased risk of death (OR, 2.42; 95% CI, 1.13-5.18). Specific management should be implemented for cancer survivors. More intense management against smoking is necessary, as continued smoking in cancer survivors may increase the risk of second primary cancer. Moreover, cancer survivors are at a high risk of heart disease; thus, additional care should be taken. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) is released by activated platelets and induces the differentiation of T-helper 17 from naïve T cells. Contact between blood and cellulose acetate (CA) beads induces cytokine release, although their inflammatory effects on TGF-β release are unclear. We aimed to clarify the effect of CA beads on the release of TGF-β in vitro. We incubated peripheral blood with and without CA beads and measured platelets and TGF-β. Compared with blood samples incubated without beads, the platelet count and amount of TGF-β significantly decreased in blood samples incubated with CA beads. In conclusion, CA beads inhibited the release of TGF-β from adsorbed platelets. The biological effects of this reduction of TGF-β release during platelet adsorption to CA beads need further clarification. [ABSTRACT FROM AUTHOR]

Aim The aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long-term outcomes in Japanese patients with primary biliary cirrhosis ( PBC). Methods Biochemical response to ursodeoxycholic acid ( UDCA) or UDCA plus bezafibrate was defined as good (≤upper limit of normal [ ULN]), fair (≤1.5 × ULN) or poor (>1.5 × ULN) at 2 years after initiation of UDCA treatment. Associations between various factors (including age, sex, autoantibody status and histological variables at baseline), biochemical response to treatment and long-term outcomes were evaluated in 164 Japanese PBC patients. Results Anti-gp210 positivity and a higher bile duct loss score were significant risk factors for worse alkaline phosphatase ( ALP) response (odds ratios [ OR], 2.78 and 1.85, respectively). Age, anti-gp210 positivity and anticentromere positivity were significant risk factors for worse alanine aminotransferase ( ALT) response ( OR, 1.05, 4.0 and 2.77, respectively). Anti-gp210 positivity and a higher hepatitis score were significant risk factors for worse immunoglobulin ( Ig) M response ( OR, 2.10 and 2.06, respectively). Worse ALP and IgM response were significant risk factors for progression to late-stage disease without jaundice ( OR, 2.27 and 2.32, respectively). Worse ALT response was a significant risk factor for progression to late-stage disease with persistent jaundice ( OR, 11.11). Conclusion Biochemical response to treatment at 2 years, which is influenced by autoantibody status and histological variables at baseline, can predict long-term outcomes in Japanese patients with PBC. [ABSTRACT FROM AUTHOR]

The present report describes a rare case of esophageal carcinoid tumor that was treated by endoscopic resection. A 43-year-old woman underwent esophagogastroduodenoscopy at her family clinic for screening of the upper digestive tract and a small lesion resembling a submucosal tumor was detected in the lower esophagus. A biopsy sample from the lesion was diagnosed as esophageal carcinoid tumor and the patient visited our hospital for detailed examination. The tumor was approximately 3 mm in diameter and its surface appeared to be covered with normal squamous epithelium. The tumor had a shiny reddish surface without ulceration or erosion. Magnifying endoscopy with narrow-band imaging showed structures resembling reticular vessels under the epithelium. Endoscopic ultrasonography depicted the tumor as a low-echoic mass within the lamina propria. Computed tomography did not detect the tumor and no metastatic lesions were evident in other organs. With the patient's informed consent, the tumor was resected using endoscopic submucosal dissection, with a sufficient free margin in both the vertical and horizontal directions. Magnifying endoscopic examination showed the resected tumor to have abundant reticular vessels. Finally, the tumor was diagnosed immunopathologically as an esophageal carcinoid tumor (neuroendocrine cell tumor, grade 1), without lymphatic or vascular invasion. [ABSTRACT FROM AUTHOR]

Objective A higher plasma aldosterone-renin ratio ( ARR) is an established marker for screening for primary aldosteronism ( PA). The association between higher ARR and mortality in a general population has not been fully explored. We here examined whether higher ARR is a risk factor for total and cause-specific mortality in a Japanese population. Subjects and Methods A population-based, longitudinal study of 1,310 Japanese individuals (age: 63·9 ± 9·8 years) enrolled in the Takahata study between 2004 and 2006 and followed for up to 8 years. The incidence and causes of death were monitored annually until 10 January 2012 (median follow-up: 2691 days). Results During the follow-up period, 64 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total and cancer mortality in subjects with lower ARR (log-rank P < 0·001). Cox's proportional hazard model analyses with adjustment for age and gender showed that lower ARR was associated with increased total and cancer mortality in subjects with low (≦72) vs high (>72) ARR (hazard ratios and 95% confidential intervals: 2·56, 1·44-4·56 and 2·78, 1·16-6·65, respectively). Conclusions Lower ARR was a significant and independent risk factor for increased total and cancer mortality in this Japanese population. Subjects with higher ARR were not-at-risk for total death in general. These findings increase the necessity for identifying people with PA from those with higher ARR. People with higher ARR without PA may be at very low risk for total and cancer death. [ABSTRACT FROM AUTHOR]

Aim Recently, serum levels of anti-programmed cell death-1 (anti- PD-1) antibodies have been reported to be useful for the discrimination of type 1 autoimmune hepatitis ( AIH) from drug-induced liver injury ( DILI) and to be associated with clinical features of type 1 AIH. This multicenter study aimed to validate the usefulness of serum anti- PD-1 antibody as a serological marker for type 1 AIH. Methods Serum samples before the initiation of corticosteroid treatment were obtained from 71 type 1 AIH patients and 37 DILI patients. Serum levels of anti- PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. Results Serum levels of anti- PD-1 antibodies were higher in type 1 AIH patients than in DILI patients ( P < 0.001). The receiver-operator curve analysis showed that serum levels of anti- PD-1 antibodies were useful for the discrimination of type 1 AIH from DILI (area under the curve, 0.80). On the other hand, the multivariate Cox proportional hazard model showed that positivity for serum anti- PD-1 antibody, probable diagnosis based on the revised scoring system proposed by the International Autoimmune Hepatitis Group, and prothrombin activity of less than 60% were associated with the later normalization of serum transaminase levels. During the clinical course, the disease relapsed more frequently in patients positive for serum anti- PD-1 antibody (36% vs 11%). Conclusion This study suggests that serum anti- PD-1 antibody is useful for the diagnosis of type 1 AIH as an auxiliary diagnostic marker, and that serum levels of anti- PD-1 antibodies reflect clinical features of type 1 AIH. [ABSTRACT FROM AUTHOR]

Genotype 2 hepatitis C virus ( HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy ( SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis. [ABSTRACT FROM AUTHOR]

Aim The number of Japanese patients with anorexia nervosa ( AN) is increasing as society changes. Mild liver injury is a complication of AN in around 30% of cases. In some rare instances, patients present with severe liver injury similar to acute liver failure. However, there are numerous uncertainties over the clinical characteristics of this condition. The objective of the present study was to clarify the clinical characteristics of AN complicated by liver injury and to investigate the factors related to hepatic complications. Methods Thirty-seven patients hospitalized at our institution with a diagnosis of AN were enrolled as the study subjects. The study used clinical data obtained at the time of hospitalization. The enrolled patients underwent subgroup analysis and were categorized into three groups: (i) normal alanine aminotransferase ( ALT), (ii) moderately elevated ALT, and (iii) highly elevated ALT. Results All of the study subjects were female with a median age of 24 years and presenting with marked weight loss (mean body mass index, 13 kg/m2). Thirteen of the subjects had liver injury. We found that patients in the highly elevated ALT group had a significantly high blood urea nitrogen ( BUN)/creatinine ratio, and a low blood sugar level. Conclusions Our present findings indicate that AN patients with highly elevated ALT have a severe dehydration. This suggests that dysfunction of hepatic circulation accompanying severe dehydration due to malnutrition may be an important factor in the development of liver injury in AN patients. [ABSTRACT FROM AUTHOR]

Aim This study evaluated the efficacy of interferon plus ribavirin and examined whether interleukin 28B ( IL28B) polymorphism influenced treatment outcome in Japanese patients with hepatitis C virus ( HCV)-related liver cirrhosis ( LC). Methods Fourteen collaborating centers provided details of 261 patients with HCV-related LC undergoing treatment with interferon plus ribavirin. Univariate and multivariate analyses were used to establish which factors predicted treatment outcome. Results Eighty-four patients (32.2%) achieved a sustained virological response ( SVR). SVR rates were 21.6% (41/190) in patients with HCV genotype 1 with high viral load ( G1H) and 60.6% (43/71) in patients with non- G1H. In patients with non- G1H, treatment outcome was effective irrespective of IL28B polymorphism. In those with G1H, SVR was achieved in 27.1% of patients with the IL28B rs8099917 TT allele compared with 8.8% of those with the TG/ GG alleles ( P = 0.004). In patients with G1H having TT allele, treatments longer than 48 weeks achieved significantly higher SVR rates than treatments less than 48 weeks (34.6% vs 16.4%, P = 0.042). In patients with G1H having TG/ GG alleles, treatments longer than 72 weeks achieved significantly higher SVR rates than treatments less than 72 weeks (37.5% vs 4.1%, P = 0.010). Conclusion Interferon plus ribavirin treatment in Japanese patients with non- G1H HCV-related LC was more effective than those with G1H and not influenced by IL28B polymorphism. In those with G1H, IL28B polymorphism may predict SVR and guide treatment duration: SVR rates were higher in those with the TT allele treated for more than 48 weeks and those with the TG/ GG alleles treated for more than 72 weeks. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α, ( TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes ( GMs) and implicated as a major factor in inflammatory bowel disease ( IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis ( GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate ( CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide ( LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified. [ABSTRACT FROM AUTHOR]

Background and Aim We recently encountered patients with localized esophageal eosinophilia in a small area of the esophagus. However, this condition remains to be described in detail, and its clinical significance has not been established. We investigated the clinical, endoscopic and histological features of localized esophageal eosinophilia in comparison with diffuse esophageal eosinophilia. Methods We investigated 10 patients with localized esophageal eosinophilia, and compared them with 23 who had diffuse esophageal eosinophilia. Whether esophageal eosinophilia was localized or diffuse was determined on the basis of endoscopic findings. Localized esophageal eosinophilia was defined endoscopically as a focal area of esophageal eosinophilia, whereas diffuse esophageal eosinophilia was defined as a widespread area of esophageal eosinophilia involving more than one of three locations: the upper, middle and lower esophagus. Histological esophageal eosinophilia in the mucosa showing endoscopic abnormality was confirmed by biopsy with a peak of ≥15 eosinophils/high-power field. Results There were no significant differences in age, gender distribution, allergic conditions or peripheral eosinophilia between the two groups. In all cases but one, localized esophageal eosinophilia was observed in a small area above the esophagogastric junction. Esophageal symptoms such as dysphagia, heartburn or chest pain were present in 20% of the localized group and in 65% of the diffuse group, the difference being statistically significant ( P < 0.05). The maximum amounts of eosinophils infiltrating the esophageal mucosa did not differ between the groups. Conclusions Esophageal eosinophilia can be localized in a small area, especially above the esophagogastric junction. Gastric acid reflux or contact may influence this condition in addition to its allergic pathogenesis. [ABSTRACT FROM AUTHOR]

Although erythroid abnormalities (anemia and polycythemia) are commonly observed pathological conditions, not much information about borderline abnormalities is available. In this study, a cross-sectional study to analyze the relationships between erythropoiesis and nutrition, physical features, and laboratory test findings was conducted in middle-aged and older men and women. The study included 3519 Japanese people (1579 men and 1940 women), age 40 years and over. Analysis of variance showed that the group with a tendency to anemia was older, had a lower body mass index and diastolic blood pressure, and had higher serum adiponectin and creatinine. Multiple regression analysis showed that adiponectin, triglycerides, and total protein were common factors that affected erythropoiesis in both men and women. Hepatic, renal, and cardiac functions were also factors involved in erythropoiesis in men and in postmenopausal women. In addition, nutrient factors such as alcohol, vitamins, and carbohydrates were also significantly involved in erythropoiesis in men, but there were no significant nutrient factors involved in erythropoiesis in either premenopausal or postmenopausal women. This study showed that factors that influence erythropoiesis differ between men, premenopausal women, and postmenopausal women, and it suggested that appropriately modifying erythropoiesis management for each group of people is essential. [ABSTRACT FROM AUTHOR]

Deep sequencing technologies are currently cutting edge, and are opening fascinating opportunities in biomedicine, producing over 100-times more data compared to the conventional capillary sequencers based on the Sanger method. Next-generation sequencing ( NGS) is now generally defined as the sequencing technology that, by employing parallel sequencing processes, producing thousands or millions of sequence reads simultaneously. Since the GS20 was released as the first NGS sequencer on the market by 454 Life Sciences, the competition in the development of the new sequencers has become intense. In this review, we describe the current deep sequencing systems and discuss the application of advanced technologies in the field of hepatology. [ABSTRACT FROM AUTHOR]

Prolactin is not only a pituitary hormone but an immunoregulatory hormone secreted from lymphocytes. Prolactin induction in relation to hepatitis C virus (HCV) infection has not been elucidated. The serum levels of prolactin were examined in 232 HCV-infected subjects positive for anti-HCV antibody and 65 healthy controls negative for it, who were recruited in the cohort study. The prolactin mRNAs were measured in peripheral blood mononuclear cells (PBMCs) of eleven healthy volunteers including five men and six women before and after stimulation by HCV in vitro. The serum level of prolactin and prolactin mRNA in PBMCs were measured by chemiluminescence immunoassay and real-time PCR, respectively. The serum levels of prolactin were significantly higher in the HCV-infected subjects (median: 7.5, IQR: 5.7-10.9 ng/ml) than in the controls (median: 5.6, IQR: 4.4-8.3 ng/ml) ( P < 0.01). They were significantly higher in HCV-infected males (median: 8.0, IQR: 5.9-11.8 ng/ml) than in the controls (median: 4.8, IQR: 4.2-5.9 ng/ml) ( P < 0.001), however, the difference was not significant between HCV-infected females (median: 7.3, IQR: 5.6-10.5 ng/ml) and the controls (median: 6.4, IQR: 5.3-9.8 ng/ml). The mRNA expression of prolactin was induced in PBMCs of all males, but it was induced in PBMCs of the two of six females examined in vitro. These results suggest that the serum level of prolactin is higher in HCV-infected males than in healthy males, and that HCV infection induces the mRNA expression of prolactin in PBMCs that is more apparent in male than in females. J. Med. Virol. 85:1199-1205, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: The extracellular hepatitis C virus (HCV)-antigen, including HCV-Core protein, can suppress immune cells. Recently, the efficacy of double filtration plasmapheresis (DFPP) for chronic hepatitis C (CHC) was reported. However, the mechanism of efficacy of DFPP might not be only the reduction of HCV but also the effect of immune cells via direct and/or indirect mechanisms. The aim of this study is to analyze the virological and immunological parameters of difficult-to-treat HCV patients treated with DFPP combined with Peg-interferon and RBV (DFPP/Peg-IFN/RBV) therapy. Methods: Twelve CHC patients were enrolled and treated with DFPP/Peg-IFN/RBV therapy. The immunological, virological and genetic parameters were studied. Results: All patients (4/4) treated with the major IL28B allele (T/T) could achieve complete early virological response (EVR). The amounts of HCV-Core antigen in the peripheral blood of EVR patients treated with DFPP/Peg-IFN/RBV rapidly declined in comparison to those of late virological response (LVR) patients treated with DFPP/Peg-IFN/RBV and EVR patients treated with Peg-IFN and RBV (Peg-IFN/RBV). The amount of IFN-γ produced from peripheral blood gradually increased. On the other hand, the amount of IL10 gradually decreased in the EVR patients. The frequencies of HCV-Core binding on CD3+ T cells rapidly declined in EVR patients treated with DFPP/Peg-IFN/RBV therapy. Moreover, the distributions of activated CD4+and CD8+ T cells and CD16-CD56 high natural killer cells were significantly changed between before and after DFPP. Conclusions: The rapid reduction of HCV-Core antigens and changes in the distribution of lymphoid cells could contribute to the favorable immunological response during DFPP/Peg-IFN/RBV therapy. [ABSTRACT FROM AUTHOR]

Several host and viral factors have been reported to influence the effectiveness of pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. In Japan, where the age of treated patients is comparatively high, recent studies have reported poor response to treatment in older female patients, but little is known about the relationship between advanced age in women and previously reported factors. Using a database of 1167 patients chronically infected with hepatitis C virus (HCV) genotype 1b, we analyzed the amino acid sequences of the HCV core protein and interferon sensitivity determining region (ISDR) and examined the relationships among predictive factors. The proportion of patients with substitutions at core 70, which is associated with poor response to pegylated interferon plus ribavirin therapy, increased with age only in female patients. A similar trend was observed for ISDR wild type (wt). We also found that core 70 wt is associated with core 91 wt ( P = 5.4 × 10) as well as ISDR wt ( P = 0.025). HCV RNA levels were higher in patients with core and ISDR wt ( P < 0.001). Furthermore, core amino acid mutations were associated with advanced fibrosis and higher inflammatory activity ( P = 0.028 and 0.048, respectively) as well as higher gamma-glutamyltranspeptidase, alanine aminotransferase and low-density lipoprotein cholesterol levels ( P < 0.001, 0.006 and 0.001, respectively). A combination of factors account for poor response rate in older female patients in Japan. Elucidating the relationship between amino acid substitutions and metabolic alteration is an important step in understanding the mechanism of HCV interferon resistance. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM+ subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM− subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/γcnull (NOG) mice, revealed that a smaller number of EpCAM+ cells (minimum 100) than EpCAM− cells was necessary for tumor formation. The bifurcated differentiation of EpCAM+ cell clones into both EpCAM+ and EpCAM− cells was obvious both in vitro and in vivo, but EpCAM− clones sustained their phenotype. These clonal analyses suggested that EpCAM+ cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM+ clones, but not into EpCAM− clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM+ and EpCAM− cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM+ population is biologically quite different from the EpCAM− population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC. ( Cancer Sci 2010) [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is characterized by unknown etiologies, anti-mitochondrial antibodies, injury of the biliary duct and the lack of a definite remedy. The etiologies of PBC have been well-discussed, including microorganisms and xenobiotics as the triggers for initiating the disease, and an abnormality of immune-tolerance. Recently, several animal models of PBC have been developed that may lead to the development of new therapies. Here, we reviewed the articles that address the etiology of PBC and the therapy for this disease for the confirmation of our current positions and future directions. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a “drug-free state” is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24–48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 103/mm3 and less than 7 log copies of HBV DNA, also, long-term IFN for 24–48 weeks is indicated. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted. [ABSTRACT FROM AUTHOR]

Background/Aims: Biliary atresia (BA) is a progressive disease characterized by bile duct inflammation and fibrosis. The aetiology is unknown and may be due to a virus-induced, autoimmune-mediated injury of cholangiocytes. Cholangiocytes are not only targets of injury but may also modulate hepatic inflammation. The aim of this study was to determine the immune profile of murine cholangiocytes and the ability to function as antigen-presenting cells (APCs) in culture with Rhesus rotavirus (RRV), poly I:C (viral mimic) or interferon-γ/tumour necrosis factor-α. Methods/Results: Both the cholangiocyte cell line (long-term culture) and fresh, ex vivo cholangiocytes expressed APC surface markers major histocompatibility complex (MHC)-class I and II and CD40, while only the cultured cell line expressed costimulatory molecules B7-1 and B7-2. Despite APC expression, cultured cholangiocytes were unable to function as competent APCs in T-cell proliferation assays. Furthermore, both cultured and ex vivo cholangiocytes expressed RNA transcripts for many pro-inflammatory cytokines and chemokines. Conclusions: Although cholangiocytes contain APC molecules, they are incompetent at antigen presentation and cannot elicit effective T-cell activation. Upregulation of MHC-class I and II found in BA mice may serve to prime the cholangiocyte as a target for immune-mediated injury. Cholangiocytes produced many pro-inflammatory cytokines and chemokines in the setting of RRV infection and T-helper type 1 cytokine milieu, suggesting a role of cholangiocytes as immune modulators promoting the ongoing inflammation that exists in RRV-induced BA. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected ‘accidentally’ (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program. [ABSTRACT FROM AUTHOR]