Orlistat Reverse Fatty Infiltration and Improves Hepatic Fibrosis in Obese Patients with Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.     

Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis

Background and AimsIron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH.MethodsMale mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet.ResultsrAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the in vivo findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation.ConclusionsOverexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.     

Yo Jyo Hen Shi Ko (YHK) Improves Transaminases in Nonalcoholic Steatohepatitis (NASH): A Randomized Pilot Study

NASH is a common condition with a rising incidence. There is progression to cirrhosis in some cases and the potential for mortality or requirement of liver transplantation. Currently, there is no approved therapy for NASH. The natural compound YHK has both anti-inflammatory and antifibrotic properties, and can lead to improvement in transaminases in viral hepatitis. Improvement in transaminases may correlate with improved histology in NASH and hence may impact on the natural history. We sought to determine the effects of YHK on NASH. We performed a randomized, double-blind, placebo-controlled pilot study to determine the effects of YHK on transaminases and on quality of life (QoL) in patients with biopsy-confirmed NASH and a persistently abnormal ALT or AST. Eight patients were randomized to YHK or placebo for 8 weeks. The ALT and AST were measured at baseline and weeks 4, 8, and 12. SF-36 surveys were serially completed. All five patients in the YHK group but none in the placebo group had a marked decrease in ALT at both week 4 and week 8 compared to baseline. After discontinuing YHK the ALT returned toward baseline at week 12. The mean decrease in ALT compared to baseline was significantly greater in the YHK group than in the placebo group at both week 4 (−42.8 ± 23.2 vs. −6.3 ± 6.7 U/L; P = 0.036) and week 8 (−45.4 ± 23.4 vs. 6.0 ± 24.6 U/L; P = 0.036). There was also a nonsignificant decrease in AST in the YHK group compared to placebo. QoL was not affected and no severe adverse events were reported. In this controlled pilot study we found the novel nutraceutical agent YHK to be effective at reducing ALT values in patients with NASH. YHK is well tolerated. Further studies are justified to assess the impact of YHK in the natural history of NASH. This study was funded by Kyotsu Jigyo, Inc., Japan.     

Serum Ferritin Is a Clinical Biomarker in Japanese Patients with Nonalcoholic Steatohepatitis (NASH) Independent of HFE Gene Mutation

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Iron is regarded as a putative element that interacts with oxygen radicals, and high rates of hyperferritinemia and increased hepatic iron stores have been demonstrated in NASH. We investigated serum ferritin concentrations, HFE gene mutations, and insulin resistance in Japanese NASH patients and the diagnostic utility of serum ferritin concentrations as a means of distinguishing NASH. Serum ferritin concentrations were measured in 86 patients with histopathologically verified NAFLD (24 with steatosis and 62 with NASH) and 20 control subjects, they were tested for HFE gene mutations and their insulin resistance was measured. The serum ferritin concentration was significantly higher in the NASH patients than in the patients with simple steatosis (P = 0.006). There was no significant difference between the groups in HFE gene mutation (C282Y, H63D, and S65C), and the serum ferritin level was related with insulin resistance. The area under the ROC curve was 0.732 for distinguishing NASH from simple steatosis (P = 0.005; 95% CI, 0.596–0.856). In conclusion high serum ferritin concentrations are a distinguishing feature of Japanese NASH patients independent of HFE gene mutations.     

非酒精性脂肪性肝病和非酒精性脂肪性肝炎的无创性诊断

非酒精性脂肪性肝病（NAFLD）在美国和世界上许多其他地区都是最常见的慢性肝病．其患病率持续上升,目前美国约1,4的成人和10％的儿童患NAFLD。NAFLD包括多种疾病状态,从通常呈良性、非进展性临床过程的单纯性脂肪肝直至更为严重的、可进展为肝硬化和终末期肝病的非酒精性脂肪性肝炎（NASH）。目前．NASH的诊断依赖于创伤性肝活检,而肝活检存在取样和读片误差的缺陷。NASH的临床危险因素包括糖尿病和代谢综合征．但这些因素本身不足以预测NASH。常规肝酶水平预测可靠性低,新型血浆肝细胞死亡标记物单独或与临床危险因素联合今后可能成为无创性诊断工具。本文对无创性诊断工具在鉴别单纯性脂肪肝与NASH以及确定肝纤维化的存在及其范围中的作用作一概述．