Ryujin Endo

Interleukin-17 as a new marker of severity of acute hepatic injury.

Aim:  To determine cytokines associated with the progression of acute hepatic injury (AHI), we comprehensively evaluated the serum levels of 17 cytokines.

Epidemiological and clinical study of sporadic acute hepatitis E caused by indigenous strains of hepatitis E virus in Japan compared with acute hepatitis A.

BackgroundWe compared acute hepatitis E (AH-E) and acute hepatitis A (AH-A) to investigate the epidemiology, clinical features, and prognosis of AH-E caused by an indigenous hepatitis E virus (HEV) in Japan.MethodsWe enrolled 58 patients diagnosed with AH-A or AH-E (32 men and 26 women; age, 20–72 years) from December 1997 to October 2002. Phylogenetic analysis of the partial 412-nucleotide sequence of open reading frame (ORF) 2 was performed in patients with AH-E.ResultsRegarding the geographic distribution of the HEV genotype, genotype III was principally distributed in Honshu Island, and genotype IV in Hokkaido Island (P = 0.0034). The phylogenetic analysis of the ORF2 region revealed that there were significant geographic differences in the distribution of the HEV strains in Japan, with some strains being widespread and some, localized. In comparison with AH-A patients, those with AH-E were older (56.1 ± 10.6 vs 45.9 ± 10.8 years; P = 0.0017). The proportion of males among patients with AH-E was significantly higher (P = 0.0001). Pyrexia was often observed in AH-A, and malaise in AH-E. Laboratory data indicate that AH-E induces a weak immunological reaction, whereas jaundice appears earlier in AH-E than in AH-A. One patient with AH-E died of acute hepatic failure, but none of those with AH-A died during the study period.ConclusionsOur results suggest that there are geographical differences between HEV strains in Japan, and that AH-E is more common in males and older patients than AH-A. Laboratory data indicate a weak immunological reaction and early appearance of jaundice in AH-E.

The Tohoku Medical Megabank Project: Design and Mission

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

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.

Initial load of hepatitis B virus (HBV), its changing profile, and precore/core promoter mutations correlate with the severity and outcome of acute HBV infection

BackgroundThe pathogenesis of the fulminant or severe form of acute hepatitis B virus (HBV) infection remains unclear, although both host- and virus-specific factors are considered to have a great impact on the c course. We aimed to define possible viral factors implicated in the severe form of acute HBV infection.MethodsWe investigated viral factors in 42 patients with acute HBV infection: 11 had fulminant hepatitis (FH); 9 had a severe form of acute hepatitis (SAH), defined as having a prothrombin activity of less than 40% without encephalopathy; and 22 had acute self-limited hepatitis (AH).ResultsAlthough there was no significant difference in serum HBV DNA levels on admission among the three groups, the level decreased more rapidly in patients with SAH or FH than in those with AH. In patients with SAH or FH, the HBV load on admission was higher in patients who died than in those who recovered (7.0 ± 1.6 vs 5.6 ± 1.0 log copies/ml; P = 0.0293). In univariate analysis, seronegativity for hepatitis B envelope antigen (HBeAg) and mutations in both the precore (G1896A and/or G1899A) and core promoter (T1753A/C and/or T1754C/G and/or A1762T/G1764A) were associated with FH (odds ratio [OR], 5.60; P = 0.0269 and OR, 52.0; P = 0.0006; respectively). In multivariate logistic regression analysis, only the presence of precore/core promoter mutations was associated with FH (OR, 42.8; P = 0.0020).ConclusionsThe rapid decrease in viral load in the early phase of acute HBV infection was associated with the severity of the disease. A high viral load on admission and the presence of both precore and core promoter mutations in patients with severe coagulopathy closely correlated with mortality.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial.

Background and Aim:  This prospective control study examined whether supplementation with branched‐chain amino acid (BCAA)‐enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA).

Early prediction of short-term development of hepatic encephalopathy in patients with acute liver disease unrelated to paracetamol. A prospective study in Japan☆

BACKGROUND/AIMS The aim of our study was to provide a predictive model for early recognition of the risk of short-term development of hepatic encephalopathy (HE) in patients with symptomatic acute liver disease (ALD). METHODS From a retrospective analysis of 220 patients with ALD, prothrombin time (PT) equal to, or lower than, 80% of normal, was set as the registration criteria in the subsequent patient cohorts of the study. Then, a HE-prediction model was derived by a logistic regression analysis of data in 259 new patients, and prospectively validated in 124 other patients, both groups of patients were affected by ALD unrelated to paracetamol (non-P ALD). RESULTS The following HE-prediction model was established: lambda = [0.692 x ln(1 + total bilirubin(mg/dL))] - 0.065 x PT(%) + [1.388 x Age(years)] + [0.868 x Etiology] - 1.156, where Age is 1 in patients older than 50 years and Etiology is 1 when the cause of non-P ALD is flare-up of type B hepatitis, auto-immune hepatitis or unknown, and 0 otherwise. In the validation group, according to the model-based risk of subsequent development of HE, sensitivity and specificity of the model were 100% and 69.0%, respectively, in patients with an evaluated risk lower than 20%, and 62.5% and 93.1%, respectively, in those with an evaluated risk equal to, or greater than, 50%. CONCLUSION In Japanese patients with symptomatic non-P ALD, our model, which includes four of the five items used in the Kings College Hospital criteria, represents an acceptable, effective model to allow early detection of the risk of short-term development of HE. Using this model in other populations requires further validation specific to each of them.

Guidelines on nutritional management in Japanese patients with liver cirrhosis from the perspective of preventing hepatocellular carcinoma

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.

Effect of zinc on liver cirrhosis with hyperammonemia: A preliminary randomized, placebo-controlled double-blind trial

OBJECTIVE To our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. METHODS Patients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (≤65 μg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. RESULTS Blood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. CONCLUSION Although this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings.

Prediction of Hepatic Encephalopathy Development in Patients With Severe Acute Hepatitis

To identify factors predicting the development of hepatic encephalopathy, 164 patients with severe acute hepatitis (SAH), defined as acute hepatitis having a prolonged prothrombin time (PT) of < 40% activity but without hepatic encephalopathy, were prospectively observed at 57 major liver centers in Japan. From the data of 65 patients enrolled from 1997 to 1998, a prediction equation was developed by multiple logistic regression analysis and prospectively evaluated using the data of 99 patients since 1999. Of the 164 patients with SAH, 51 (31%) developed hepatic encephalopathy. From the etiologic viewpoint, the percentages of patients developing encephalopathy were highest in non–A-E hepatitis (41.9%). A predictive model, logit(p) = 0.084 × age (year)+ 0.129 × serum total bilirubin (TB, in mg/dL)–0.158× prothrombin time (%)–2.434, was developed. In conclusion, old age, prolonged PT, elevation of TB, and non–A-E hepatitis are potential risk factors for developing encephalopathy in SAH.