Tetsuya Yasunaka

Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice.

Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen‐rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine‐choline–deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen‐rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor‐α, interleukin‐6, fatty acid synthesis–related genes, oxidative stress biomarker 8‐hydroxydeoxyguanosine (8‐OHdG), and apoptosis marker terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling (TUNEL)–positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator‐activated receptor‐α expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH‐related hepatocarcinogenesis model. Eight‐week‐old male STAM mice were divided into three experimental groups as follows: (1) control water (CW‐STAM); (2) hydrogen‐rich water (HW‐STAM); and (3) pioglitazone (PGZ‐STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW‐STAM and PGZ‐STAM groups than in the CW‐STAM group. The maximum tumor size was smaller in the HW‐STAM group than in the other groups. Conclusion: Consumption of hydrogen‐rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912–921)

Autoimmune hepatitis with acute presentation in Japan

BACKGROUND In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently. AIM We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation. METHODS Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation. RESULTS Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation. CONCLUSIONS In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients.

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% α-tocopherol (α-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial β-oxidation and redox system.

Clinical features of autoimmune hepatitis diagnosed based on simplified criteria of the International Autoimmune Hepatitis Group

BACKGROUND Recently, simplified diagnostic criteria for autoimmune hepatitis have been proposed. AIM We aimed to evaluate usefulness of the simplified criteria. METHODS We applied the simplified criteria to 176 autoimmune hepatitis patients diagnosed according to the revised scoring system proposed in 1999 (original criteria). Furthermore, in order to compare predictabilities between these two diagnostic criteria, we included 168 patients with other liver disease than autoimmune hepatitis. RESULTS Of 176 autoimmune hepatitis patients, 85% were diagnosed with autoimmune hepatitis according to the simplified criteria, and patients diagnosed according to the simplified criteria showed a higher frequency of antinuclear antibodies and/or smooth muscle antibodies of 1:80 or greater and slightly higher serum levels of immunoglobulin G than those diagnosed according to the original criteria. However, 30% of male patients, 23% of patients with acute presentation, 50% of patients showing histological acute hepatitis and 46% of patients negative for antinuclear antibodies at presentation were not diagnosed with autoimmune hepatitis according to the simplified criteria. The simplified criteria showed lower sensitivity (85% vs. 100%) and higher specificity (99% vs. 93%) for autoimmune hepatitis than the original criteria. CONCLUSIONS The simplified criteria may be useless for the diagnosis of patients with atypical features, especially patients with histological acute hepatitis.

Long-term outcome and hepatocellular carcinoma development in chronic hepatitis B or cirrhosis patients after nucleoside analog treatment with entecavir or lamivudine.

Aim:  We conducted this prospective study to elucidate the long‐term outcome and incidence of hepatocellular carcinoma (HCC) development after nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB) or cirrhosis.

Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid

Background and Aim:  Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA.

Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC).

Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis

Aim:  Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20–30% of patients are negative for ANA. We assessed the clinical features of ANA‐negative patients.

Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C.

Chronic infection with hepatitis C virus (HCV) decreases health‐related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms.

Serum oxidative–anti‐oxidative stress balance is dysregulated in patients with hepatitis C virus‐related hepatocellular carcinoma

Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti‐oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti‐oxidative stress in CLD patients.