Yoshio Tokumoto

Real‐time tissue elastography for evaluation of hepatic fibrosis and portal hypertension in nonalcoholic fatty liver diseases

The aim of this study was to prospectively measure liver stiffness with real‐time tissue elastography in patients with nonalcoholic fatty liver diseases (NAFLD) and to compare the result with the clinical assessment of fibrosis using histological stage. One hundred and eighty‐one prospectively enrolled patients underwent real‐time tissue elastography, with the first 106 being analyzed as the training set and the remaining 75 being evaluated as the validation set. Hepatic and splenic elastic ratios were calculated and compared with stage of histological fibrosis. Portal hypertension (PH) was assessed. Real‐time tissue elastography cut‐off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut‐off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%‐96.0% in all stages. Only portal fibrosis correlated with the hepatic elastic ratio by multivariate analysis. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Patients with PH, defined by splenic elasticity, had early fibrosis. Patients with severe PH were found only in the group with cirrhosis. Conclusion: Real‐time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. (HEPATOLOGY 2012)

Recent clinical features of Wilson’s disease with hepatic presentation

BackgroundWe carried out this study to evaluate recent clinical features of Wilson’s disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC).MethodsSixteen patients with hepatic manifestations were diagnosed with WD in the period 1976–2003. We divided this period into two periods, “past” and “recent”. The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital.ResultsFour patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects.ConclusionsRecently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

Amino acid imbalance in patients with chronic liver diseases.

Aim:  The aim of this study is to clarify the amino acid imbalance in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC).

Aerobic exercise improves insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus

Aim:  Hepatitis C virus infection often complicates glucose intolerance, which can be caused by insulin resistance. Aerobic exercise can improve insulin resistance and decrease body fat in patients with diabetes. The aim of the present study is to clarify whether aerobic exercise improves insulin resistance and decreases body fat in patients with chronic hepatitis C (CH‐C).

Diabetes mellitus reduces the therapeutic effectiveness of interferon-α2b plus ribavirin therapy in patients with chronic hepatitis C

Aim:  Patients with chronic hepatitis C (CHC) often have diabetes mellitus (DM). However, it is unknown whether DM affects patient response to interferon (IFN) plus ribavirin therapy. Therefore, the aim of this study was to examine the influence of DM on the outcome of IFN‐α2b plus ribavirin therapy.

Change of acute hepatitis B transmission routes in Japan.

Background. Many years have passed since various prophylactic policies for preventing hepatitis B virus (HBV) transmission were begun. We studied the chronological alterations in HBV infectious routes in patients with acute hepatitis B in the past 27 years. Methods. Seventy-two patients with acute HBV infection who were admitted to our hospital during the period 1976 to 2002 were enrolled in this study. This study was divided into two periods (first period, 1976–1990; and second period, 1991–2002), and the HBV infectious routes were studied. Results. Infectious routes have been changing. Posttransfusion hepatitis was seen only in the first period. In the second period, sexual transmission was the major infectious route (68%), followed by infection at a medical facility or occupational exposure such as needlestick injury (8%). Conclusions. Transmission from sexual contact has become the main infectious route of HBV in Japan.

Blockade of B-cell-activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity

Chronic inflammation is an important contributor to the development and progression of metabolic syndrome. Recent evidence indicates that, in addition to innate immune cells, adaptive immune cells have an important role in this process. We previously showed that the serum level of B-cell-activating factor (BAFF) was increased in patients with nonalcoholic steatohepatitis. However, it is currently unknown whether BAFF and BAFF-R (BAFF-R) have a role in lipid metabolism in the liver. To address this issue, the role played by BAFF and BAFF-R signaling in the development of insulin resistance and hepatic steatosis was examined in BAFF-R−/− mice fed a high-fat diet (HFD). Furthermore, the effect of BAFF on lipid metabolism in hepatocytes was analyzed in vitro. BAFF-R−/− mice showed improvements in HFD-induced obesity and insulin resistance. In addition, the number of B cells, levels of serum IgG, and inflammation of visceral fat were reduced in these mice. However, the expression of steatogenic genes and fatty acid deposition in the liver was higher in these mice than in control mice. BAFF was also found to downregulate the expression of steatogenesis genes and enhance steatosis in hepatocytes through BAFF-R. Collectively, these data indicated that, in addition to its known functions in inflammation and glucose metabolism, BAFF has a protective role in hepatic steatosis by regulating lipid metabolism in the liver.

Non-alcoholic fatty liver disease: factors associated with its presence and onset.

Non‐alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. Therefore, the detection of early‐stage NAFLD is important. Many studies have described the factors that predict the presence of NAFLD and its onset, and several markers have been identified. These markers have enabled the identification of high‐risk patients and have improved routine medical practice. To prevent advanced disease, clinicians need to have simple markers that predict the onset of NAFLD so that interventions can be started at much earlier stages of disease. This review summarizes the current state of knowledge regarding independent factors, as reported in large studies, that predict the presence of NAFLD and its onset, especially markers that can be used in daily medical practice, such as physical measurements and blood tests.

Protein Kinase R Modulates c-Fos and c-Jun Signaling to Promote Proliferation of Hepatocellular Carcinoma with Hepatitis C Virus Infection

Double-stranded RNA-activated protein kinase R (PKR) is known to be upregulated by hepatitis C virus (HCV) and overexpressed in hepatocellular carcinoma (HCC). However, the precise roles of PKR in HCC with HCV infection remain unclear. Two HCV replicating cell lines (JFH-1 and H77s), generated by transfection of Huh7.5.1 cells, were used for experiments reported here. PKR expression was modulated with siRNA and a PKR expression plasmid, and cancer-related genes were assessed by real-time PCR and Western blotting; cell lines were further analyzed using a proliferation assay. Modulation of genes by PKR was also assessed in 34 human HCC specimens. Parallel changes in c-Fos and c-Jun gene expression with PKR were observed. Levels of phosphorylated c-Fos and c-Jun were upregulated by an increase of PKR, and were related to levels of phosphorylated JNK1 and Erk1/2. DNA binding activities of c-Fos and c-Jun also correlated with PKR expression, and cell proliferation was dependent on PKR-modulated c-Fos and c-Jun expression. Coordinate expression of c-Jun and PKR was confirmed in human HCC specimens with HCV infection. PKR upregulated c-Fos and c-Jun activities through activation of Erk1/2 and JNK1, respectively. These modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could be an attractive therapeutic target.

Neuropsychiatric dysfunction in patients with chronic hepatitis and liver cirrhosis

Aim:  The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC).