Michihiro Nonaka

Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-alpha) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-alpha were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, -21%) and C20:4,n-6 (arachidonic acid, -22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.

Elevated levels of serum advanced glycation end products in patients with non-alcoholic steatohepatitis

Background and Aim:  Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, play important roles in the pathogenesis of diabetic vascular complications. Recently, AGE have also been found to be involved in insulin resistance. Although non‐alcoholic steatohepatitis (NASH) is generally considered a hepatic manifestation of insulin resistance, there are no reports showing the link of AGE to NASH. The aim of this study was to evaluate the clinical significance of AGE in patients with NASH.

Analysis of delayed bleeding after endoscopic submucosal dissection for gastric epithelial neoplasms.

Aim. Delayed bleeding after endoscopic submucosal dissection (ESD) for gastric epithelial neoplasms is a major complication. We investigated factors related to post-ESD bleeding to identify preventive measures. Methods. The study included 161 gastric epithelial neoplasms in 142 patients from June 2007 to September 2010. Post-ESD bleeding was defined as an ulcer with active bleeding or apparent exposed vessels diagnosed by an emergency endoscopy or a planned follow-up endoscopy. We analyzed associations between bleeding and the following factors: age, sex, morphology, pathology, tumor depth, ulcer presence/absence, location, size of the resected lesion, duration of the procedure, the number of times bleeding occurred during ESD, and the use of anticoagulants and/or antiplatelet drugs. Subsequently, we examined characteristics of bleeding cases. Results. Post-ESD bleeding occurred in 21 lesions. Univariate analysis of these cases showed that ulcer presence/absence (P < 0.001), middle or lower third lesions (P = 0.036), circumference (P = 0.014), and a post-ESD ulcer with an extended lesser curve (P = 0.009) were significant predictors of bleeding. Multivariate analysis showed that ulcer presence/absence (OR 9.73, 95% CI 2.28–41.53) was the only significant predictor. Conclusion. Ulcer presence/absence was considered the most significant predictor of post-ESD bleeding.

Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b : A randomized controlled trial

Chronic HCV–infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG‐IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG‐IFN/RBV. Eighty‐four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG‐IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG‐IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG‐IFN/RBV in HCV genotype 1b–infected patients.

Cytoprotective effect of tauroursodeoxycholate on hepatocyte apoptosis induced by peroxisome proliferator-activated receptor gamma ligand.

Background and Aim:  Peroxisome proliferator‐activated receptor gamma (PPARγ) ligands inhibit cell growth and induce apoptosis in various cancer cells. Bile acids are also known to cause hepatocyte apoptosis through nuclear receptor‐mediated mechanisms. The aim of this study was to examine the effect of two different bile acid species on the inhibitory action of PPARγ in cell growth with paying attention to the role of the mitogen‐activated protein kinase pathway as an underlying mechanism.

Comparison of Outcome of Hepatic Arterial Infusion Chemotherapy Combined with Radiotherapy and Sorafenib for Advanced Hepatocellular Carcinoma Patients with Major Portal Vein Tumor Thrombosis

Objective: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT). Methods: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh ≤7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician. Results: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14–3.57; p = 0.01) as a significant and independent determinant of overall survival. Conclusions: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib.

Comparison of clinical outcome of hepatic arterial infusion chemotherapy and sorafenib for advanced hepatocellular carcinoma according to macrovascular invasion and transcatheter arterial chemoembolization refractory status: Distinguish between HAIC and SOR

Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies.

Effect of prolonged administration of pegylated interferon/ribavirin therapy in genotypes 2a and 2b: propensity score-matched analysis.

Chronic hepatitis C genotype 2 patients show high susceptibility to pegylated interferon plus ribavirin therapy (PEG/RBV). However, the differences in response to therapy between genotypes 2a and 2b, and the efficacy of prolonged therapy for refractory patients have not been evaluated. We investigated the differences in response to PEG/RBV between each genotype and examined the efficacy of prolonged therapy.

S1899 Genetic Ablation of Bach1 Followed By Upregulation of Heme Oxygenase-1 Improved Nonalcoholic Steatohepatitis in Rodent Model

Backgrounds/Aims: Bach1 is a transcriptional repressor of heme oxygenase-1 (HO-1). HO1 has cytoprotective activities through its antioxidant and anti-inflammatory properties. In this study, we investigated the effect of bach1 knockout on an animal model of NASH. Methods: Ten-week old male C57BL/6J mice (WT) and bach1 deficient mice (KO) were pair-fed either a chow or methionine/choline deficient (MCD) diet for 8 weeks (n=15 each). At fixed periods, mice were sacrificed, and livers and blood were collected. Histological findings were assessed by HE and Azan-Mallory staining. Serum transaminases were analyzed enzymatically. Hepatic mRNA expression of HO-1, TGF-β1, αSMA, peroxisome proliferator activated receptor α (PPARα) and microsomal triglyceride transfer protein (MTP) were analyzed by real-time PCR. Hepatic content of triglycerides (TG) was analyzed enzymatically. As the determination of hepatic oxidative stress generation, hepatic malondialdehyde (MDA) content was analyzed enzymatically. Results: Whereas MCD diet promoted significantly greater weight loss (chow -15%; MCD -40%, P < 0.05), significant change was not observed between WT and KO mice on each diet. At 8 weeks on MCD diet, liver inflammation and steatosis were pathohistologically significantly attenuated in KO mice when compared with WT mice, but changes found in the serum level of ALT were not significant. The expression of hepatic HO-1 mRNA was increased in KO mice when compared with WT mice (6.1fold). Upregulation of hepatic MDA content by MCD diet (4.2-fold) was inhibited in KO mice thoroughly. MCD diet feeding increased hepatic content of TG in WT mice (6.1-fold). But, in KO mice, such change was repressed significantly. In WT mice, MCD diet reduced hepatic PPARα and MTP mRNA expression significantly, whereas such a change was not observed in KO mice. Hepatic expression of TGF-β1 and αSMA mRNA was expressed at higher levels in WT mice after 1 and 4 weeks on the MCD diet when compared to KO mice. Such changes were not observed in WT and KO mice on chow diet. Conclusions: Up-regulation of HO-1 induced by Gene ablation of bach1 improved steatosis, at least in part, through themechanism of hepatic secretion of TG associated with PPARα-MTP pathway. HO-1 also inhibited ROS generation in the liver and suppressed the activation of hepatic stellate cells, suggesting its causal relation to liver fibrosis. We speculate that HO-1 plays a protective role in the development of NASH through its cytoprotective and anti-oxidant activities.